58 results on '"Lindenmeyer M"'
Search Results
2. Vangl2, a planar cell polarity molecule, is implicated in irreversible and reversible kidney glomerular injury
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Papakrivopoulou, Eugenia, Vasilopoulou, E., Lindenmeyer, M., Pacheco, Sabrina, Brzoska, Hortensja L., Price, Karen L., Kolatsi-Joannou, Maria, White, Kathryn E., Henderson, Deborah J., Dean, Charlotte H., Cohen, Clemens D., Salama, Alan D., Woolf, Adrian S., and Long, David A.
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Adult ,Male ,matrix metalloproteinase ,podocyte ,kidney disease ,Kidney Glomerulus ,glomerulus ,planar cell polarity ,Nerve Tissue Proteins ,urologic and male genital diseases ,Young Adult ,Animals ,Humans ,Cells, Cultured ,Mice, Knockout ,Original Paper ,urogenital system ,Glomerulosclerosis, Focal Segmental ,Podocytes ,Nephrosis, Lipoid ,Intracellular Signaling Peptides and Proteins ,Cell Polarity ,Membrane Proteins ,Middle Aged ,Original Papers ,QR ,Enzyme Activation ,Mice, Inbred C57BL ,Disease Models, Animal ,Matrix Metalloproteinase 9 ,Case-Control Studies ,Female ,Signal Transduction - Abstract
Planar cell polarity (PCP) pathways control the orientation and alignment of epithelial cells within tissues. Van Gogh‐like 2 (Vangl2) is a key PCP protein that is required for the normal differentiation of kidney glomeruli and tubules. Vangl2 has also been implicated in modifying the course of acquired glomerular disease, and here, we further explored how Vangl2 impacts on glomerular pathobiology in this context. Targeted genetic deletion of Vangl2 in mouse glomerular epithelial podocytes enhanced the severity of not only irreversible accelerated nephrotoxic nephritis but also lipopolysaccharide‐induced reversible glomerular damage. In each proteinuric model, genetic deletion of Vangl2 in podocytes was associated with an increased ratio of active‐MMP9 to inactive MMP9, an enzyme involved in tissue remodelling. In addition, by interrogating microarray data from two cohorts of renal patients, we report increased VANGL2 transcript levels in the glomeruli of individuals with focal segmental glomerulosclerosis, suggesting that the molecule may also be involved in certain human glomerular diseases. These observations support the conclusion that Vangl2 modulates glomerular injury, at least in part by acting as a brake on MMP9, a potentially harmful endogenous enzyme. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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- 2018
3. Genetic Background but Not Intestinal Microbiota After Co-Housing Determines Hyperoxaluria-Related Nephrocalcinosis in Common Inbred Mouse Strains
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Ma, Q., Grigorescu, M., Schreiber, A., Kettritz, R., Lindenmeyer, M., Anders, H.J., and Steiger, S.
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Mice, Knockout ,Hyperoxaluria ,Calcium Oxalate ,uromodulin ,Immunology ,kidney stone disease ,Housing, Animal ,Gastrointestinal Microbiome ,mouse strains ,Disease Models, Animal ,Mice ,Nephrocalcinosis ,Cardiovascular and Metabolic Diseases ,microbiota ,Animals ,Immunology and Allergy ,Original Research - Abstract
Calcium oxalate (CaOx) crystal formation, aggregation and growth is a common cause of kidney stone disease and nephrocalcinosis-related chronic kidney disease (CKD). Genetically modified mouse strains are frequently used as an experimental tool in this context but observed phenotypes may also relate to the genetic background or intestinal microbiota. We hypothesized that the genetic background or intestinal microbiota of mice determine CaOx crystal deposition and thus the outcome of nephrocalcinosis. Indeed, Casp1(-/-), Cybb(-/-) or Casp1(-/-)/Cybb(-/-) knockout mice on a 129/C57BL/6J (B6J) background that were fed an oxalate-rich diet for 14 days did neither encounter intrarenal CaOx crystal deposits nor nephrocalcinosis-related CKD. To test our assumption, we fed C57BL/6N (B6N), 129, B6J and Balb/c mice an oxalate-rich diet for 14 days. Only B6N mice displayed CaOx crystal deposits and developed CKD associated with tubular injury, inflammation and interstitial fibrosis. Intrarenal mRNA expression profiling of 64 known nephrocalcinosis-related genes revealed that healthy B6N mice had lower mRNA levels of uromodulin (Umod) compared to the other three strains. Feeding an oxalate-rich diet caused an increase in uromodulin protein expression and CaOx crystal deposition in the kidney as well as in urinary uromodulin excretion in B6N mice but not 129, B6J and Balb/c mice. However, backcrossing 129 mice on a B6N background resulted in a gradual increase in CaOx crystal deposits from F2 to F7, of which all B6N/129 mice from the 7th generation developed CaOx-related nephropathy similar to B6N mice. Co-housing experiments tested for a putative role of the intestinal microbiota but B6N co-housed with 129 mice or B6N/129 (3rd and 6th generation) mice did not affect nephrocalcinosis. In summary, genetic background but not the intestinal microbiome account for strain-specific crystal formation and, the levels of uromodulin secretion may contribute to this phenomenon. Our results imply that only littermate controls of the identical genetic background strain are appropriate when performing knockout mouse studies in this context, while co-housing is optional.
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- 2021
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4. Wnt Pathway Regulation in Chronic Renal Allograft Damage
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von Toerne, C., Schmidt, C., Adams, J., Kiss, E., Bedke, J., Porubsky, S., Gretz, N., Lindenmeyer, M. T., Cohen, C. D., Gröne, H.-J., and Nelson, P. J.
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- 2009
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5. Collagen type VIII expression in human diabetic nephropathy
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Gerth, J., Cohen, C. D., Hopfer, U., Lindenmeyer, M. T., Sommer, M., Gröne, H. J., and Wolf, G.
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- 2007
6. Microarray analysis reveals influence of the sesquiterpene lactone parthenolide on gene transcription profiles in human epithelial cells
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Lindenmeyer, M. T., Kern, C., Sparna, T., Donauer, J., Wilpert, J., Schwager, J., Porath, D., Kreutz, C., Timmer, J., and Merfort, I.
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- 2007
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7. New sesquiterpene lactones from Arnica tincture prepared from fresh flowerheads of Arnica montana
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Kos, O., Lindenmeyer, M. T., Tubaro, Aurelia, Sosa, Silvio, Merfort, I., Kos, O., Lindenmeyer, M. T., Tubaro, Aurelia, Sosa, Silvio, and Merfort, I.
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Anti-inflammatory activity ,Arnia montana ,Asteraceae - Published
- 2005
8. Anti-GBM glomerulonephritis involves IL-1 but is independent of NLRP3/ASC inflammasome-mediated activation of caspase-1
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Lichtnekert, J, Kulkarni, O P, Mulay, S R, Rupanagudi, K V, Ryu, M, Allam, R, Vielhauer, V, Muruve, D, Lindenmeyer, M T, Cohen, C D, Anders, H J, and University of Zurich
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1000 Multidisciplinary ,1300 General Biochemistry, Genetics and Molecular Biology ,570 Life sciences ,biology ,610 Medicine & health ,10035 Clinic for Nephrology ,1100 General Agricultural and Biological Sciences ,10052 Institute of Physiology - Published
- 2011
9. Human nephrosclerosis triggers a hypoxia-related glomerulopathy
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Neusser, M A, Lindenmeyer, M T, Moll, A G, Segerer, S, Edenhofer, I, Sen, K, Stiehl, D P, Kretzler, M, Gröne, H J, Schlöndorff, D, Cohen, C D, and University of Zurich
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2734 Pathology and Forensic Medicine ,10076 Center for Integrative Human Physiology ,570 Life sciences ,biology ,610 Medicine & health ,10029 Clinic and Policlinic for Internal Medicine ,10052 Institute of Physiology - Published
- 2010
10. Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses
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Starke, A, Lindenmeyer, M T, Segerer, S, Neusser, M A, Rüsi, B, Schmid, D M, Cohen, C D, Wüthrich, R P, Fehr, T, Waeckerle-Men, Y, University of Zurich, and Fehr, T
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10062 Urological Clinic ,2727 Nephrology ,10076 Center for Integrative Human Physiology ,570 Life sciences ,biology ,610 Medicine & health ,10035 Clinic for Nephrology ,10052 Institute of Physiology - Published
- 2010
11. Patients with IgA nephropathy exhibit high systemic PDGF-DD levels
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Boor, P, Eitner, F, Cohen, C D, Lindenmeyer, M T, Mertens, P R, Ostendorff, T, Floege, J, University of Zurich, and Boor, P
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2727 Nephrology ,2747 Transplantation ,570 Life sciences ,biology ,610 Medicine & health ,10035 Clinic for Nephrology ,10052 Institute of Physiology - Published
- 2009
12. Transcript-specific expression profiles derived from sequence-based analysis of standard microarrays
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Moll, A G, Lindenmeyer, M T, Kretzler, M, Nelson, P J, Zimmer, R, Cohen, C D, University of Zurich, and Moll, A G
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1000 Multidisciplinary ,1300 General Biochemistry, Genetics and Molecular Biology ,570 Life sciences ,biology ,610 Medicine & health ,10035 Clinic for Nephrology ,1100 General Agricultural and Biological Sciences ,10052 Institute of Physiology - Published
- 2009
13. Alterations of the podocyte proteome in response to high glucose concentrations
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Schordan, S, Schordan, E, Lindenmeyer, M T, Cohen, C D, Endlich, K, Maurer, M, University of Zurich, and Endlich, K
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1303 Biochemistry ,1312 Molecular Biology ,570 Life sciences ,biology ,610 Medicine & health ,10035 Clinic for Nephrology ,10052 Institute of Physiology - Published
- 2009
14. Genomic Analysis in Nephrology – towards Systems Biology and Systematic Medicine?
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Neusser, M A, Lindenmeyer, M T, Kretzler, M, Cohen, C D, University of Zurich, and Cohen, C D
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2727 Nephrology ,10076 Center for Integrative Human Physiology ,570 Life sciences ,biology ,610 Medicine & health ,10035 Clinic for Nephrology ,10052 Institute of Physiology - Published
- 2008
15. Loss of endogenous thymosin β4 accelerates glomerular disease
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Vasilopoulou, E, Kolatsi-Joannou, M, Lindenmeyer, M, White, K, Robson, M, Cohen, C, Sebire, N, Riley, P, Winyard, P, and Long, D
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podocyte ,Nephrology ,inflammation ,urogenital system ,fibrosis ,cytoskeleton ,glomerulus ,urologic and male genital diseases ,hormones, hormone substitutes, and hormone antagonists - Abstract
Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin \(\beta_4\) regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin \(\beta_4\) improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin \(\beta_4\) in the kidney is unknown. We demonstrate that thymosin β4 is expressed prominently in podocytes of developing and adult mouse glomeruli. Global loss of thymosin \(\beta_4\) did not affect healthy glomeruli, but accelerated the severity of immune-mediated nephrotoxic nephritis with worse renal function, periglomerular inflammation, and fibrosis. Lack of thymosin \(\beta_4\) in nephrotoxic nephritis led to the redistribution of podocytes from the glomerular tuft toward the Bowman capsule suggesting a role for thymosin \(\beta_4\) in the migration of these cells. Thymosin \(\beta_4\) knockdown in cultured podocytes also increased migration in a wound-healing assay, accompanied by F-actin rearrangement and increased RhoA activity. We propose that endogenous thymosin \(\beta_4\) is a modifier of glomerular injury, likely having a protective role acting as a brake to slow disease progression.
16. The SVX II silicon vertex detector upgrade at CDF
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Antos, J., Chao, H-Y., Chang, P., Cheng, M-T., Chu, M-L., Guo, R-S., Ho, C-L., Teng, P-K., Wang, M-J., Wu, S-C., Yeh, G-P, Yeh, P., Andressen, J., Barsotti, E., Bowden, M., Cihangir, S., Gonzalez, H., Grimm, C., Haynes, B., Hrycyk, M., Howell, J., Husby, D., Knopf, W., Lindenmeyer, M., Ratzmann, P., Sarge, J., Spalding, J., Spiegel, L., Tkaczyk, S., Woodbury, K., Yarema, R., Zimmerman, S., Zimmerman, T., Gay, C., Huth, J., Oliver, J., Spiropulu, M., Stroehmer, R., Iwata, Y., Ohmoto, T., Ohsugi, T., Barnett, B., Skarha, J., Snider, R., Takashima, R., Ely, R., Garcia-Sciveres, M., Haber, C., Milgrome, O., Lu, L., Bailey, M., Bruner, N., Gold, M., Hoeferkamp, M., Matthews, J., Moore, E., Seidel, S., Thomas, T., Worm, S., Yu, L., Kohriki, T., Unno, Y., Tamura, N., Bacchetta, N., Bisello, D., Bolla, G., Boudreau, J., Engels, E., Jr., Huffman, B.T., Shepard, P.F., Rosatti, R., Bedeschi, F., Menzione, A., Punzi, G., Ristori, L., Zetti, F., Bortoletto, D., Garfinkel, A., Hardmann, A., Hoffman, K., Keaffaber, T., Shaw, N.M., Cassada, J., Tipton, P., Conway, J., Done, J., Kamon, T., Tannenbaum, B., Wolinski, J., Benjamin, D., Frautschi, M., Sill, A., and Hou, J-F.
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- 1996
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17. The SVX II silicon vertex detector upgrade at CDF
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Antos, J., Chao, H-Y., Cheng, M-T., Chu, M-L., Guo, R-S., Ho, C-L., Teng, P-K., Wang, M-J., Wu, S-C., Yeh, G-P., Yeh, P., Blucher, E., Frisch, H., Sullivan, G., Barsotti, E., Cihangir, S., Gonzalez, H., Hrycyk, M., Lindenmeyer, M., Pawlak, J., Ratzmann, P., Spalding, J., Spiegel, L., Swoboda, C., Yarema, R., Zimmerman, S., Zimmerman, T., Gay, C., Huth, J., Oliver, J., Iwata, Y., Ohmoto, T., Ohsugi, T., Barnett, B., Cammerata, J., Skarha, J., Bruner, N., Frautschi, M., Gold, M., Hoeferkamp, M., Kingsberry, P., Matthews, J., Yu, L., Seidel, S., Thomas, T.L., Wells, S., Tamura, N., Bacchetta, N., Bisello, D., Castro, A., Paccagnella, A., Boudreau, J., Engels, E., Jr., Hu, P., Huffman, T., Shepard, P., Vandenbrink, S., Bedeschi, F., Belforte, S., Bonaccorso, C., Franceschi, A., Galeotti, S., Giannetti, P., Menzione, A., Morsani, F., Dell'Orso, M., Punzi, G., Raffaelli, F., Ristori, L., Zetti, F., Bortoletto, D., Garfinkel, A., Hardmann, A., Hoffman, K., Shaw, N.M., Done, J., Kamon, T., Scarpine, V., Trost, H.-J., Wolinski, J., Benjamin, D., Sill, A., Hou, J-F., Ely, R., Haber, C., Kipnis, I., Kleinfelder, S., and Milgrome, O.
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- 1995
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18. Compartment specific expression of dendritic cell markers in human glomerulonephritis.
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Segerer, S., Heller, F., Lindenmeyer, M. T., Schmid, H., Cohen, C. D., Draganovici, D., Mandelbaum, J., Nelson, P. J., Gröne, H.-J., Gröne, E. F., Figel, A.-M., Nössner, E., and Schlöndorff, D.
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MACROPHAGES , *DENDRITIC cells , *ANTIGEN presenting cells , *LYMPHOID tissue , *BONE marrow , *IMMUNOHISTOCHEMISTRY , *HISTOCHEMISTRY - Abstract
Macrophages and dendritic cells are heterogenous and highly plastic bone marrow-derived cells that play major roles in renal diseases. We characterized these cells using immunohistochemistry in 55 renal biopsies from control patients or patients with glomerulonephritis as an initial step towards postulating specific roles for these cells in kidney disease. In proliferative glomerulonephritis numerous CD68 positive (pan monocyte, macrophage and dendritic marker) cells were found in both glomeruli and the tubulointerstitial space, however, a myeloid dendritic cell marker (DC-SIGN) was identified only in the tubulointerstitium. A significant number of plasmacytoid dendritic cells (identified as BDCA-2 positive cells) were seen at sites of interstitial inflammation, including follicular aggregates of inflammatory cells. Langerin positive cells (a marker of Langerhans' cells) were detectable but rare. The area of either CD68 or DC-SIGN positive interstitial cells correlated with serum creatinine. Low levels of DC-SIGN, DC-LAMP and MHC class II mRNA were present in the tubulointerstitial space in controls and increased only in that region in proliferative glomerulonephritis. We demonstrate that the CD68 positive cells infiltrating the glomerulus lack dendritic cell markers (reflecting macrophages), whereas in the tubulointerstitial space the majority of CD68 positive cells are also DC-SIGN positive (reflecting myeloid dendritic cells). Their number correlated with serum creatinine, which further emphasizes the significance of interstitial DCs in progressive glomerular diseases.Kidney International (2008) 74, 37–46; doi:10.1038/ki.2008.99; published online 26 March 2008 [ABSTRACT FROM AUTHOR]
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- 2008
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19. Optimized protocol for the multi-omics processing of cryopreserved human kidney tissue.
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Gies SE, Hänzelmann S, Kylies D, Lassé M, Lagies S, Hausmann F, Khatri R, Zolotarev N, Poets M, Zhang T, Demir F, Billing AM, Quaas J, Meister E, Engesser J, Mühlig AK, Lu S, Liu S, Chilla S, Edenhofer I, Czogalla J, Braun F, Kammerer B, Puelles VG, Bonn S, Rinschen MM, Lindenmeyer M, and Huber TB
- Abstract
Biobanking of tissue from clinically obtained kidney biopsies for later use with multi-omic and imaging techniques is an inevitable step to overcome the need of disease model systems and towards translational medicine. Hence, collection protocols ensuring integration into daily clinical routines using preservation media not requiring liquid nitrogen but instantly preserving kidney tissue for clinical and scientific analyses are of paramount importance. Thus, we modified a robust single nucleus dissociation protocol for kidney tissue stored snap frozen or in the preservation media RNA later and CellCover. Using porcine kidney tissue as surrogate for human kidney tissue, we conducted single nucleus RNA sequencing with the Chromium 10X Genomics platform. The resulting data sets from each storage condition were analyzed to identify any potential variations in transcriptomic profiles. Furthermore, we assessed the suitability of the preservation media for additional analysis techniques (proteomics, metabolomics) and the preservation of tissue architecture for histopathological examination including immunofluorescence staining. In this study, we show that in daily clinical routines the RNA later facilitates the collection of highly preserved human kidney biopsies and enables further analysis with cutting-edge techniques like single nucleus RNA sequencing, proteomics, and histopathological evaluation. Only metabolome analysis is currently restricted to snap frozen tissue. This work will contribute to build tissue biobanks with well-defined cohorts of the respective kidney disease that can be deeply molecularly characterized, opening new horizons for the identification of unique cells, pathways and biomarkers for the prevention, early identification, and targeted therapy of kidney diseases.
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- 2024
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20. Zyxin is important for the stability and function of podocytes, especially during mechanical stretch.
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Kliewe F, Siegerist F, Hammer E, Al-Hasani J, Amling TRJ, Hollemann JZE, Schindler M, Drenic V, Simm S, Amann K, Daniel C, Lindenmeyer M, Hecker M, Völker U, and Endlich N
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- Humans, Mice, Animals, Zyxin genetics, Zyxin metabolism, Actin Cytoskeleton metabolism, Kidney Glomerulus, Focal Adhesions metabolism, Podocytes metabolism, Hypertension, Renal, Nephritis
- Abstract
Podocyte detachment due to mechanical stress is a common issue in hypertension-induced kidney disease. This study highlights the role of zyxin for podocyte stability and function. We have found that zyxin is significantly up-regulated in podocytes after mechanical stretch and relocalizes from focal adhesions to actin filaments. In zyxin knockout podocytes, we found that the loss of zyxin reduced the expression of vinculin and VASP as well as the expression of matrix proteins, such as fibronectin. This suggests that zyxin is a central player in the translation of mechanical forces in podocytes. In vivo, zyxin is highly up-regulated in patients suffering from diabetic nephropathy and in hypertensive DOCA-salt treated mice. Furthermore, zyxin loss in mice resulted in proteinuria and effacement of podocyte foot processes that was measured by super resolution microscopy. This highlights the essential role of zyxin for podocyte maintenance in vitro and in vivo, especially under mechanical stretch., (© 2024. The Author(s).)
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- 2024
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21. GDF-15 Suppresses Puromycin Aminonucleoside-Induced Podocyte Injury by Reducing Endoplasmic Reticulum Stress and Glomerular Inflammation.
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von Rauchhaupt E, Klaus M, Ribeiro A, Honarpisheh M, Li C, Liu M, Köhler P, Adamowicz K, Schmaderer C, Lindenmeyer M, Steiger S, Anders HJ, and Lech M
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- Humans, Mice, Animals, Puromycin Aminonucleoside adverse effects, Puromycin Aminonucleoside metabolism, Growth Differentiation Factor 15 genetics, Growth Differentiation Factor 15 metabolism, Creatinine metabolism, Inflammation metabolism, Mice, Knockout, Podocytes metabolism, Kidney Diseases metabolism
- Abstract
GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15 -deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15 -deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.
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- 2024
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22. Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase regulation in chronic kidney disease.
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Faivre A, Dissard R, Kuo W, Verissimo T, Legouis D, Arnoux G, Heckenmeyer C, Fernandez M, Tihy M, Rajaram RD, Delitsikou V, Le NA, Spingler B, Mueller B, Shulz G, Lindenmeyer M, Cohen C, Rutkowski JM, Moll S, Scholz CC, Kurtcuoglu V, and de Seigneux S
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- Humans, Animals, Mice, X-Ray Microtomography, Repressor Proteins genetics, Down-Regulation, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mixed Function Oxygenases genetics, Mixed Function Oxygenases metabolism, Hypoxia
- Abstract
Background: The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents have yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases. While prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase factor inhibiting HIF (FIH)., Methods: We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-computed tomography imaging. We analysed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies of various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach to assess its relevance in CKD., Results: In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with decreased development of fibrosis., Conclusions: The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seems promising in proteinuric kidney disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
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- 2023
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23. Kidney outcome after mild to moderate COVID-19.
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Schmidt-Lauber C, Hänzelmann S, Schunk S, Petersen EL, Alabdo A, Lindenmeyer M, Hausmann F, Kuta P, Renné T, Twerenbold R, Zeller T, Blankenberg S, Fliser D, and Huber TB
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- Humans, SARS-CoV-2, Albuminuria, Cohort Studies, Prospective Studies, Pandemics, Hematuria, Cross-Sectional Studies, Kidney, Disease Progression, COVID-19 complications, COVID-19 epidemiology, Pyuria
- Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a remarkable kidney tropism. While kidney effects are common in severe coronavirus disease 2019 (COVID-19), data on non-severe courses are limited. Here we provide a multilevel analysis of kidney outcomes after non-severe COVID-19 to test for eventual kidney sequela., Methods: This cross-sectional study investigates individuals after COVID-19 and matched controls recruited from the Hamburg City Health Study (HCHS) and its COVID-19 program. The HCHS is a prospective population-based cohort study within the city of Hamburg, Germany. During the COVID-19 pandemic the study additionally recruited subjects after polymerase chain reaction-confirmed SARS-CoV-2 infections. Matching was performed by age, sex and education. Main outcomes were estimated glomerular filtration rate (eGFR), albuminuria, Dickkopf3, haematuria and pyuria., Results: A total of 443 subjects in a median of 9 months after non-severe COVID-19 were compared with 1328 non-COVID-19 subjects. The mean eGFR was mildly lower in post-COVID-19 than non-COVID-19 subjects, even after adjusting for known risk factors {β = -1.84 [95% confidence interval (CI) -3.16 to -0.52]}. However, chronic kidney disease [odds ratio (OR) 0.90 (95% CI 0.48-1.66)] or severely increased albuminuria [OR 0.76 (95% CI 0.49-1.09)] equally occurred in post-COVID-19 and non-COVID-19 subjects. Haematuria, pyuria and proteinuria were also similar between the two cohorts, suggesting no ongoing kidney injury after non-severe COVID-19. Further, Dickkopf3 was not increased in the post-COVID-19 cohort, indicating no systematic risk for ongoing GFR decline [β = -72.19 (95% CI -130.0 to -14.4)]., Conclusion: While mean eGFR was slightly lower in subjects after non-severe COVID-19, there was no evidence for ongoing or progressive kidney sequela., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
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- 2023
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24. The ShGlom Assay Combines High-Throughput Drug Screening With Downstream Analyses and Reveals the Protective Role of Vitamin D3 and Calcipotriol on Podocytes.
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Ristov MC, Lange T, Artelt N, Nath N, Kuss AW, Gehrig J, Lindenmeyer M, Cohen CD, Gul S, Endlich K, Völker U, and Endlich N
- Abstract
Chronic kidney disease (CKD) is a major public health burden affecting more than 500 million people worldwide. Podocytopathies are the main cause for the majority of CKD cases due to pathogenic morphological as well as molecular biological alterations of postmitotic podocytes. Podocyte de-differentiation is associated with foot process effacement subsequently leading to proteinuria. Since currently no curative drugs are available, high throughput screening methods using a small number of animals are a promising and essential tool to identify potential drugs against CKD in the near future. Our study presents the implementation of the already established mouse Glom Assay as a semi-automated high-throughput screening method-shGlom Assay -allowing the analysis of several hundreds of FDA-verified compounds in combination with downstream pathway analysis like transcriptomic and proteomic analyses from the same samples, using a small number of animals. In an initial prescreening we have identified vitamin D3 and its analog calcipotriol to be protective on podocytes. Furthermore, by using RT-qPCR, Western blot, and RNA sequencing, we found that mRNA and protein expression of nephrin, the vitamin D receptor and specific podocyte markers were significantly up-regulated due to vitamin D3- and calcipotriol-treatment. In contrast, kidney injury markers were significantly down-regulated. Additionally, we found that vitamin D3 and calcipotriol have had neither influence on the expression of the miR-21 and miR-30a nor on miR-125a/b, a miRNA described to regulate the vitamin D receptor. In summary, we advanced the established mouse Glom Assay to a semi-automated high-throughput assay and combined it with downstream analysis techniques by using only a minimum number of animals. Hereby, we identified the vitamin D signaling pathway as podocyte protective and to be counteracting their de-differentiation., Competing Interests: JG is an employee of the DITABIS AG, Pforzheim, Germany and the ACQUIFER Imaging GmbH, Heidelberg, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ristov, Lange, Artelt, Nath, Kuss, Gehrig, Lindenmeyer, Cohen, Gul, Endlich, Völker and Endlich.)
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- 2022
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25. Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease.
- Author
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Verissimo T, Faivre A, Rinaldi A, Lindenmeyer M, Delitsikou V, Veyrat-Durebex C, Heckenmeyer C, Fernandez M, Berchtold L, Dalga D, Cohen C, Naesens M, Ricksten SE, Martin PY, Pugin J, Merlier F, Haupt K, Rutkowski JM, Moll S, Cippà PE, Legouis D, and de Seigneux S
- Subjects
- Animals, Humans, Kidney metabolism, Kidney Tubules, Proximal metabolism, Mice, Retrospective Studies, Gluconeogenesis physiology, Renal Insufficiency, Chronic metabolism
- Abstract
Introduction: CKD is associated with alterations of tubular function. Renal gluconeogenesis is responsible for 40% of systemic gluconeogenesis during fasting, but how and why CKD affects this process and the repercussions of such regulation are unknown., Methods: We used data on the renal gluconeogenic pathway from more than 200 renal biopsies performed on CKD patients and from 43 kidney allograft patients, and studied three mouse models, of proteinuric CKD (POD-ATTAC), of ischemic CKD, and of unilateral urinary tract obstruction. We analyzed a cohort of patients who benefitted from renal catheterization and a retrospective cohort of patients hospitalized in the intensive care unit., Results: Renal biopsies of CKD and kidney allograft patients revealed a stage-dependent decrease in the renal gluconeogenic pathway. Two animal models of CKD and one model of kidney fibrosis confirm gluconeogenic downregulation in injured proximal tubule cells. This shift resulted in an alteration of renal glucose production and lactate clearance during an exogenous lactate load. The isolated perfused kidney technique in animal models and renal venous catheterization in CKD patients confirmed decreased renal glucose production and lactate clearance. In CKD patients hospitalized in the intensive care unit, systemic alterations of glucose and lactate levels were more prevalent and associated with increased mortality and a worse renal prognosis at follow-up. Decreased expression of the gluconeogenesis pathway and its regulators predicted faster histologic progression of kidney disease in kidney allograft biopsies., Conclusion: Renal gluconeogenic function is impaired in CKD. Altered renal gluconeogenesis leads to systemic metabolic changes with a decrease in glucose and increase in lactate level, and is associated with a worse renal prognosis., (Copyright © 2022 by the American Society of Nephrology.)
- Published
- 2022
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26. α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier.
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Rogg M, Maier JI, Van Wymersch C, Helmstädter M, Sammarco A, Lindenmeyer M, Zareba P, Montanez E, Walz G, Werner M, Endlich N, Benzing T, Huber TB, and Schell C
- Subjects
- Animals, Integrins metabolism, Mice, Mice, Knockout, Glomerular Filtration Barrier metabolism, Microfilament Proteins metabolism, Podocytes metabolism
- Abstract
Background: The cell-matrix adhesion between podocytes and the glomerular basement membrane is essential for the integrity of the kidney's filtration barrier. Despite increasing knowledge about the complexity of integrin adhesion complexes, an understanding of the regulation of these protein complexes in glomerular disease remains elusive., Methods: We mapped the in vivo composition of the podocyte integrin adhesome. In addition, we analyzed conditional knockout mice targeting a gene ( Parva ) that encodes an actin-binding protein (α-parvin), and murine disease models. To evaluate podocytes in vivo , we used super-resolution microscopy, electron microscopy, multiplex immunofluorescence microscopy, and RNA sequencing. We performed functional analysis of CRISPR/Cas9-generated PARVA single knockout podocytes and PARVA and P ARVB double knockout podocytes in three- and two-dimensional cultures using specific extracellular matrix ligands and micropatterns., Results: We found that PARVA is essential to prevent podocyte foot process effacement, detachment from the glomerular basement membrane, and the development of FSGS. Through the use of in vitro and in vivo models, we identified an inherent PARVB -dependent compensatory module at podocyte integrin adhesion complexes, sustaining efficient mechanical linkage at the filtration barrier. Sequential genetic deletion of PARVA and PARVB induces a switch in structure and composition of integrin adhesion complexes. This redistribution of these complexes translates into a loss of the ventral actin cytoskeleton, decreased adhesion capacity, impaired mechanical resistance, and dysfunctional extracellular matrix assembly., Conclusions: The findings reveal adaptive mechanisms of podocyte integrin adhesion complexes, providing a conceptual framework for therapeutic strategies to prevent podocyte detachment in glomerular disease., (Copyright © 2022 by the American Society of Nephrology.)
- Published
- 2022
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27. GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus.
- Author
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Lorenz G, Ribeiro A, von Rauchhaupt E, Würf V, Schmaderer C, Cohen CD, Vohra T, Anders HJ, Lindenmeyer M, and Lech M
- Subjects
- Humans, Mice, Animals, Mice, Inbred C57BL, Disease Models, Animal, Ligands, Growth Differentiation Factor 15, Lupus Erythematosus, Systemic, Interferon Type I, Autoimmune Diseases
- Abstract
Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β superfamily, has been associated with acute and chronic inflammatory conditions including autoimmune disease, i.e., type I diabetes and rheumatoid arthritis. Still, its role in systemic autoimmune disease remains elusive. Thus, we studied GDF15-deficient animals in Fas-receptor intact (C57BL/6) or deficient (C57BL/6lpr/lpr) backgrounds. Further, lupus nephritis (LN) microdissected kidney biopsy specimens were analyzed to assess the involvement of GDF15 in human disease. GDF15-deficiency in lupus-prone mice promoted lymphoproliferation, T-, B- and plasma cell-expansion, a type I interferon signature, and increased serum levels of anti-DNA autoantibodies. Accelerated systemic inflammation was found in association with a relatively mild renal phenotype. Splenocytes of phenotypically overall-normal Gdf15-/- C57BL/6 and lupus-prone C57BL/6lpr/lpr mice displayed increased in vitro lymphoproliferative responses or interferon-dependent transcription factor induction in response to the toll-like-receptor (TLR)-9 ligand CpG, or the TLR-7 ligand Imiquimod, respectively. In human LN, GDF15 expression was downregulated whereas type I interferon expression was upregulated in glomerular- and tubular-compartments versus living donor controls. These findings demonstrate that GDF15 regulates lupus-like autoimmunity by suppressing lymphocyte-proliferation and -activation. Further, the data indicate a negative regulatory role for GDF15 on TLR-7 and -9 driven type I interferon signaling in effector cells of the innate immune system., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
- Published
- 2022
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28. Multiorgan tropism of SARS-CoV-2 lineage B.1.1.7.
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Ondruschka B, Heinrich F, Lindenmeyer M, Edler C, Möbius D, Czogalla J, Heinemann A, Braun F, Aepfelbacher M, Lütgehetmann M, and Huber TB
- Subjects
- Aged, Autopsy, Female, Heart virology, Humans, Kidney virology, Liver virology, Lung virology, Male, Middle Aged, Pharynx virology, SARS-CoV-2 physiology, Viral Load, Viral Tropism
- Abstract
Due to the development of novel functionalities, distinct SARS-CoV-2 variants such as B.1.1.7 fuel the current pandemic. B.1.1.7 is not only more transmissible, but may also cause an increased mortality compared to previous SARS-CoV-2 variants. Human tissue analysis of the SARS-CoV-2 lineage B.1.1.7 is urgently needed, and we here present autopsy data from 7 consecutive SARS-CoV-2 B.1.1.7 cases. The initial RT-qPCR analyses from nasopharyngeal swabs taken post mortem included typing assays for B.1.1.7. We quantitated SARS-CoV-2 B.1.1.7 viral load in autopsy tissue of multiple organs. Highest levels of SARS-CoV-2 B.1.1.7 copies normalized to ß-globin were detected in the respiratory system (lung and pharynx), followed by the liver and heart. Importantly, SARS-CoV-2 lineage B.1.1.7 was found in 100% of cases in the lungs and in 85.7% in pharynx tissue. Detection also in the kidney and brain highlighting a pronounced organ tropism. Comparison of the given results to a former cohort of SARS-CoV-2 deaths during the first wave in spring 2020 showed resembling organ tropism. Our results indicate that also SARS-CoV-2 B.1.1.7 has a relevant organ tropism beyond the respiratory tract. We speculate that B.1.1.7 spike protein's affinity to human ACE2 facilitates transmission, organ tropism, and ultimately morbidity and mortality. Further studies and larger cohorts are obligatory to proof this link., (© 2021. The Author(s).)
- Published
- 2021
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29. ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage.
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Sachs M, Wetzel S, Reichelt J, Sachs W, Schebsdat L, Zielinski S, Seipold L, Heintz L, Müller SA, Kretz O, Lindenmeyer M, Wiech T, Huber TB, Lüllmann-Rauch R, Lichtenthaler SF, Saftig P, and Meyer-Schwesinger C
- Subjects
- ADAM10 Protein genetics, Amyloid Precursor Protein Secretases genetics, Animals, Autoantibodies adverse effects, Blood Urea Nitrogen, Cadherins metabolism, Cell Adhesion, Cell Communication, Cell Membrane metabolism, Cells, Cultured, Creatinine urine, Disease Models, Animal, Female, Glomerular Filtration Barrier pathology, Glomerular Filtration Barrier physiopathology, Humans, Male, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Nephritis pathology, Nephrotic Syndrome pathology, Podocytes physiology, Proteomics, Tissue Array Analysis, Transcriptome, Wnt Signaling Pathway, ADAM10 Protein metabolism, Amyloid Precursor Protein Secretases metabolism, Membrane Proteins metabolism, Nephritis metabolism, Nephrotic Syndrome metabolism, Podocytes metabolism, Podocytes pathology, Renal Insufficiency, Chronic metabolism
- Abstract
Background: Podocytes embrace the glomerular capillaries with foot processes, which are interconnected by a specialized adherens junction to ultimately form the filtration barrier. Altered adhesion and loss are common features of podocyte injury, which could be mediated by shedding of cell-adhesion molecules through the regulated activity of cell surface-expressed proteases. A Disintegrin and Metalloproteinase 10 (ADAM10) is such a protease known to mediate ectodomain shedding of adhesion molecules, among others. Here we evaluate the involvement of ADAM10 in the process of antibody-induced podocyte injury., Methods: Membrane proteomics, immunoblotting, high-resolution microscopy, and immunogold electron microscopy were used to analyze human and murine podocyte ADAM10 expression in health and kidney injury. The functionality of ADAM10 ectodomain shedding for podocyte development and injury was analyzed, in vitro and in vivo , in the anti-podocyte nephritis (APN) model in podocyte-specific, ADAM10-deficient mice., Results: ADAM10 is selectively localized at foot processes of murine podocytes and its expression is dispensable for podocyte development. Podocyte ADAM10 expression is induced in the setting of antibody-mediated injury in humans and mice. Podocyte ADAM10 deficiency attenuates the clinical course of APN and preserves the morphologic integrity of podocytes, despite subepithelial immune-deposit formation. Functionally, ADAM10-related ectodomain shedding results in cleavage of the cell-adhesion proteins N- and P-cadherin, thus decreasing their injury-related surface levels. This favors podocyte loss and the activation of downstream signaling events through the Wnt signaling pathway in an ADAM10-dependent manner., Conclusions: ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury., (Copyright © 2021 by the American Society of Nephrology.)
- Published
- 2021
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30. Differential role of nicotinamide adenine dinucleotide deficiency in acute and chronic kidney disease.
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Faivre A, Katsyuba E, Verissimo T, Lindenmeyer M, Rajaram RD, Naesens M, Heckenmeyer C, Mottis A, Feraille E, Cippà P, Cohen C, Longchamp A, Allagnat F, Rutkowski JM, Legouis D, Auwerx J, and de Seigneux S
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury drug therapy, Acute Kidney Injury metabolism, Animals, Antineoplastic Agents toxicity, Cisplatin toxicity, Disease Progression, Humans, Male, Mice, Mice, Inbred C57BL, Niacinamide administration & dosage, Niacinamide deficiency, Pyridinium Compounds, Renal Insufficiency, Chronic chemically induced, Renal Insufficiency, Chronic drug therapy, Renal Insufficiency, Chronic metabolism, Reperfusion Injury chemically induced, Reperfusion Injury drug therapy, Reperfusion Injury metabolism, Acute Kidney Injury pathology, Disease Models, Animal, Niacinamide analogs & derivatives, Renal Insufficiency, Chronic pathology, Reperfusion Injury pathology
- Abstract
Background: Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI)., Methods: We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia-reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models., Results: RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI., Conclusion: Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
- Published
- 2021
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31. Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice.
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Moschovaki-Filippidou F, Steiger S, Lorenz G, Schmaderer C, Ribeiro A, von Rauchhaupt E, Cohen CD, Anders HJ, Lindenmeyer M, and Lech M
- Subjects
- Animals, Cell Movement genetics, Chemokine CXCL10 genetics, Chemokine CXCL10 immunology, Glomerular Basement Membrane pathology, Glomerulonephritis, Membranous genetics, Glomerulonephritis, Membranous pathology, Growth Differentiation Factor 15 genetics, Mice, Mice, Knockout, Proteinuria genetics, Proteinuria pathology, Receptors, CXCR3 genetics, Receptors, CXCR3 immunology, T-Lymphocytes pathology, Cell Movement immunology, Glomerular Basement Membrane immunology, Glomerulonephritis, Membranous immunology, Growth Differentiation Factor 15 immunology, Proteinuria immunology, T-Lymphocytes immunology
- Abstract
Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.
- Published
- 2020
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32. Soluble Uric Acid Is an Intrinsic Negative Regulator of Monocyte Activation in Monosodium Urate Crystal-Induced Tissue Inflammation.
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Ma Q, Honarpisheh M, Li C, Sellmayr M, Lindenmeyer M, Böhland C, Romagnani P, Anders HJ, and Steiger S
- Subjects
- Animals, Arthritis, Gouty chemically induced, Arthritis, Gouty genetics, Arthritis, Gouty pathology, Glucose Transport Proteins, Facilitative genetics, Glucose Transport Proteins, Facilitative immunology, Humans, Hyperuricemia chemically induced, Hyperuricemia genetics, Hyperuricemia pathology, Inflammation, Mice, Mice, Transgenic, Monocytes pathology, Solubility, Arthritis, Gouty immunology, Hyperuricemia immunology, Monocytes immunology, Uric Acid toxicity
- Abstract
Although monosodium urate (MSU) crystals are known to trigger inflammation, published data on soluble uric acid (sUA) in this context are discrepant. We hypothesized that diverse sUA preparation methods account for this discrepancy and that an animal model with clinically relevant levels of asymptomatic hyperuricemia and gouty arthritis can ultimately clarify this issue. To test this, we cultured human monocytes with different sUA preparation solutions and found that solubilizing uric acid (UA) by prewarming created erroneous results because of UA microcrystal contaminants triggering IL-1β release. Solubilizing UA with NaOH avoided this artifact, and this microcrystal-free preparation suppressed LPS- or MSU crystal-induced monocyte activation, a process depending on the intracellular uptake of sUA via the urate transporter SLC2A9/GLUT9. CD14
+ monocytes isolated from hyperuricemic patients were less responsive to inflammatory stimuli compared with monocytes from healthy individuals. Treatment with plasma from hyperuricemic patients impaired the inflammatory function of CD14+ monocytes, an effect fully reversible by removing sUA from hyperuricemic plasma. Moreover, Alb-creERT2; Glut9lox/lox mice with hyperuricemia (serum UA of 9-11 mg/dl) showed a suppressed inflammatory response to MSU crystals compared with Glut9lox/lox controls without hyperuricemia. Taken together, we unravel a technical explanation for discrepancies in the published literature on immune effects of sUA and identify hyperuricemia as an intrinsic suppressor of innate immunity, in which sUA modulates the capacity of monocytes to respond to danger signals. Thus, sUA is not only a substrate for the formation of MSU crystals but also an intrinsic inhibitor of MSU crystal-induced tissue inflammation., (Copyright © 2020 by The American Association of Immunologists, Inc.)- Published
- 2020
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33. IFN Regulatory Factor 4 Controls Post-ischemic Inflammation and Prevents Chronic Kidney Disease.
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Lorenz G, Moschovaki-Filippidou F, Würf V, Metzger P, Steiger S, Batz F, Carbajo-Lozoya J, Koziel J, Schnurr M, Cohen CD, Schmaderer C, Anders HJ, Lindenmeyer M, and Lech M
- Subjects
- Animals, Disease Models, Animal, Disease Progression, Female, Humans, Macrophage Activation genetics, Macrophage Activation immunology, Macrophages immunology, Macrophages metabolism, Mice, Mice, Knockout, Regeneration, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Disease Susceptibility, Interferon Regulatory Factors genetics, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic prevention & control, Reperfusion Injury complications, Reperfusion Injury genetics
- Abstract
Ischemia reperfusion injury (IRI) of the kidney results in interferon regulatory factor 4 (IRF4)-mediated counter-regulation of the acute inflammatory response. Beyond that, IRF4 exerts important functions in controlling the cytokine milieu, T-cell differentiation, and macrophage polarization. The latter has been implicated in tissue remodeling. It therefore remains elusive what the role of IRF4 is in terms of long-term outcome following IRI. We hypothesized that an inability to resolve chronic inflammation in Irf4
-/- mice would promote chronic kidney disease (CKD) progression. To evaluate the effects of IRF4 in chronic upon acute injury in vivo , a mouse model of chronic injury following acute IRI was employed. The expression of Irf4 increased within 10 days after IRI in renal tissue. Both mRNA and protein levels remained high up to 5 weeks upon IRI, suggesting a regulatory function in the chronic phase. Mice deficient in IRF4 display increased tubular cell loss and defective clearance of infiltrating macrophages. These phenomena were associated with increased expression of pro-inflammatory macrophage markers together with reduced expression of alternatively activated macrophage markers. In addition, IRF4-deficient mice showed defective development of alternatively activated macrophages. Hints of a residual M1 macrophage signature were further observed in human biopsy specimens of patients with hypertensive nephropathy vs. living donor specimens. Thus, IRF4 restricts CKD progression and kidney fibrosis following IRI, potentially by enabling M2 macrophage polarization and restricting a Th1 cytokine response. Deteriorated alternative macrophage subpopulations in Irf4-/- mice provoke chronic intrarenal inflammation, tubular epithelial cell loss, and renal fibrosis in the long course after IRI in mice. The clinical significance of these finding for human CKD remains uncertain at present and warrants further studies., (Copyright © 2019 Lorenz, Moschovaki-Filippidou, Würf, Metzger, Steiger, Batz, Carbajo-Lozoya, Koziel, Schnurr, Cohen, Schmaderer, Anders, Lindenmeyer and Lech.)- Published
- 2019
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34. Tubular NOX4 expression decreases in chronic kidney disease but does not modify fibrosis evolution.
- Author
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Rajaram RD, Dissard R, Faivre A, Ino F, Delitsikou V, Jaquet V, Cagarelli T, Lindenmeyer M, Jansen-Duerr P, Cohen C, Moll S, and de Seigneux S
- Subjects
- Animals, Biopsy, Diabetic Nephropathies metabolism, Diabetic Nephropathies pathology, Disease Models, Animal, Fibrosis, Gene Expression Regulation, Glomerular Filtration Rate, Humans, Hydrogen Peroxide metabolism, Kidney Tubules metabolism, Kidney Tubules pathology, Male, Mesangial Cells metabolism, Mesangial Cells pathology, Mice, Mice, Transgenic, NADPH Oxidase 4 metabolism, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Podocytes metabolism, Podocytes pathology, RNA, Messenger metabolism, Renal Insufficiency, Chronic metabolism, Renal Insufficiency, Chronic pathology, Signal Transduction, Ureteral Obstruction metabolism, Ureteral Obstruction pathology, Diabetic Nephropathies genetics, NADPH Oxidase 4 genetics, RNA, Messenger genetics, Renal Insufficiency, Chronic genetics, Ureteral Obstruction genetics
- Abstract
Background: NADPH oxidase 4 (NOX4) catalyzes the formation of hydrogen peroxide (H
2 O2 ). NOX4 is highly expressed in the kidney, but its role in renal injury is unclear and may depend on its specific tissue localization., Methods: We performed immunostaining with a specific anti-NOX4 antibody and measured NOX4 mRNA expression in human renal biopsies encompassing diverse renal diseases. We generated transgenic mice specifically overexpressing mouse Nox4 in renal tubular cells and subjected the animals to the unilateral ureteral obstruction (UUO) model of fibrosis., Results: In normal human kidney, NOX4 protein expression was at its highest on the basolateral side of proximal tubular cells. NOX4 expression increased in mesangial cells and podocytes in proliferative diabetic nephropathy. In tubular cells, NOX4 protein expression decreased in all types of chronic renal disease studied. This finding was substantiated by decreased NOX4 mRNA expression in the tubulo-interstitial compartment in a repository of 175 human renal biopsies. Overexpression of tubular NOX4 in mice resulted in enhanced renal production of H2 O2 , increased NRF2 protein expression and decreased glomerular filtration, likely via stimulation of the tubulo-glomerular feedback. Tubular NOX4 overexpression had no obvious impact on kidney morphology, apoptosis, or fibrosis at baseline. Under acute and chronic tubular injury induced by UUO, overexpression of NOX4 in tubular cells did not modify the course of the disease., Conclusions: NOX4 expression was decreased in tubular cells in all types of CKD tested. Tubular NOX4 overexpression did not induce injury in the kidney, and neither modified microvascularization, nor kidney structural lesions in fibrosis., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2019
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35. Glomerular expression pattern of long non-coding RNAs in the type 2 diabetes mellitus BTBR mouse model.
- Author
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Reichelt-Wurm S, Wirtz T, Chittka D, Lindenmeyer M, Reichelt RM, Beck S, Politis P, Charonis A, Kretz M, Huber TB, Liu S, Banas B, and Banas MC
- Subjects
- Animals, Computational Biology methods, Diabetic Nephropathies pathology, Disease Models, Animal, Gene Expression Profiling, Gene Ontology, Humans, Insulin Resistance, Kidney Glomerulus pathology, Mice, Organ Specificity genetics, RNA, Messenger genetics, Reproducibility of Results, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetic Nephropathies etiology, Gene Expression Regulation, Kidney Glomerulus metabolism, RNA, Long Noncoding genetics
- Abstract
The prevalence of type 2 diabetes mellitus (T2DM) and by association diabetic nephropathy (DN) will continuously increase in the next decades. Nevertheless, the underlying molecular mechanisms are largely unknown and studies on the role of new actors like long non-coding RNAs (lncRNAs) barely exist. In the present study, the inherently insulin-resistant mouse strain "black and tan, brachyuric" (BTBR) served as T2DM model. While wild-type mice do not exhibit pathological changes, leptin-deficient diabetic animals develop a severe T2DM accompanied by a DN, which closely resembles the human phenotype. We analyzed the glomerular expression of lncRNAs from wild-type and diabetic BTBR mice (four, eight, 16, and 24 weeks) applying the "GeneChip Mouse Whole Transcriptome 1.0 ST" array. This microarray covered more lncRNA gene loci than any other array before. Over the observed time, our data revealed differential expression patterns of 1746 lncRNAs, which markedly differed from mRNAs. We identified protein-coding and non-coding genes, that were not only co-located but also co-expressed, indicating a potentially cis-acting function of these lncRNAs. In vitro-experiments strongly suggested a cell-specific expression of these lncRNA-mRNA-pairs. Additionally, protein-coding genes, being associated with significantly regulated lncRNAs, were enriched in various biological processes and pathways, that were strongly linked to diabetes.
- Published
- 2019
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36. The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.
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Seleznik G, Seeger H, Bauer J, Fu K, Czerkowicz J, Papandile A, Poreci U, Rabah D, Ranger A, Cohen CD, Lindenmeyer M, Chen J, Edenhofer I, Anders HJ, Lech M, Wüthrich RP, Ruddle NH, Moeller MJ, Kozakowski N, Regele H, Browning JL, Heikenwalder M, and Segerer S
- Subjects
- Adult, Animals, Cell Line, Chemokines genetics, Chemokines metabolism, Disease Models, Animal, Epithelial Cells chemistry, Epithelial Cells metabolism, Female, Glomerulonephritis, IGA genetics, Humans, Immunoglobulins pharmacology, Kidney Glomerulus chemistry, Kidney Glomerulus pathology, Kidney Tubules chemistry, Kidney Tubules metabolism, Kidney Tubules pathology, Ligands, Lupus Nephritis genetics, Lymphocytes chemistry, Lymphotoxin beta Receptor analysis, Lymphotoxin beta Receptor genetics, Lymphotoxin-alpha analysis, Lymphotoxin-alpha genetics, Lymphotoxin-alpha metabolism, Lymphotoxin-beta analysis, Lymphotoxin-beta genetics, Lymphotoxin-beta metabolism, Male, Mesangial Cells metabolism, Mice, Middle Aged, Transcriptome, Glomerulonephritis, IGA metabolism, Lupus Nephritis metabolism, Lymphotoxin beta Receptor antagonists & inhibitors, Lymphotoxin beta Receptor metabolism, RNA, Messenger analysis, Signal Transduction drug effects
- Abstract
Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LTα and LTβ ligands, as well as LTβR. The LTβR protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LTβ was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LTα and LTβ mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LTβR signaling. Importantly, in a murine lupus model, LTβR blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LTβR signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases., (Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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37. BAMBI elimination enhances alternative TGF-β signaling and glomerular dysfunction in diabetic mice.
- Author
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Fan Y, Li X, Xiao W, Fu J, Harris RC, Lindenmeyer M, Cohen CD, Guillot N, Baron MH, Wang N, Lee K, He JC, Schlondorff D, and Chuang PY
- Subjects
- Angiopoietin-1 genetics, Angiopoietin-1 metabolism, Animals, Blotting, Western, Humans, In Vitro Techniques, Kidney Glomerulus pathology, Membrane Proteins genetics, Mice, Signal Transduction physiology, Smad1 Protein genetics, Smad1 Protein metabolism, Smad5 Protein genetics, Smad5 Protein metabolism, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Kidney Glomerulus metabolism, Membrane Proteins metabolism, Transforming Growth Factor beta metabolism
- Abstract
BMP, activin, membrane-bound inhibitor (BAMBI) acts as a pseudo-receptor for the transforming growth factor (TGF)-β type I receptor family and a negative modulator of TGF-β kinase signaling, and BAMBI(-/-) mice show mild endothelial dysfunction. Because diabetic glomerular disease is associated with TGF-β overexpression and microvascular alterations, we examined the effect of diabetes on glomerular BAMBI mRNA levels. In isolated glomeruli from biopsies of patients with diabetic nephropathy and in glomeruli from mice with type 2 diabetes, BAMBI was downregulated. We then examined the effects of BAMBI deletion on streptozotocin-induced diabetic glomerulopathy in mice. BAMBI(-/-) mice developed more albuminuria, with a widening of foot processes, than BAMBI(+/+) mice, along with increased activation of alternative TGF-β pathways such as extracellular signal-related kinase (ERK)1/2 and Smad1/5 in glomeruli and cortices of BAMBI(-/-) mice. Vegfr2 and Angpt1, genes controlling glomerular endothelial stability, were downmodulated in glomeruli from BAMBI(-/-) mice with diabetes. Incubation of glomeruli from nondiabetic BAMBI(+/+) or BAMBI(-/-) mice with TGF-β resulted in the downregulation of Vegfr2 and Angpt1, effects that were more pronounced in BAMBI(-/-) mice and were prevented by a MEK inhibitor. The downregulation of Vegfr2 in diabetes was localized to glomerular endothelial cells using a histone yellow reporter under the Vegfr2 promoter. Thus, BAMBI modulates the effects of diabetes on glomerular permselectivity in association with altered ERK1/2 and Smad1/5 signaling. Future therapeutic interventions with inhibitors of alternative TGF-β signaling may therefore be of interest in diabetic nephropathy., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
- Published
- 2015
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38. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors.
- Author
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Vuille-dit-Bille RN, Camargo SM, Emmenegger L, Sasse T, Kummer E, Jando J, Hamie QM, Meier CF, Hunziker S, Forras-Kaufmann Z, Kuyumcu S, Fox M, Schwizer W, Fried M, Lindenmeyer M, Götze O, and Verrey F
- Subjects
- Amino Acid Transport Systems, Neutral metabolism, Angiotensin-Converting Enzyme 2, Animals, Gene Expression drug effects, Humans, Intestines drug effects, Intestines enzymology, Membrane Transport Proteins metabolism, Peptidyl-Dipeptidase A metabolism, Protein Transport drug effects, Xenopus laevis, Amino Acid Transport Systems, Neutral genetics, Angiotensin-Converting Enzyme Inhibitors pharmacology, Intestinal Mucosa metabolism, Membrane Transport Proteins genetics, Peptidyl-Dipeptidase A genetics, Up-Regulation drug effects
- Abstract
Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression.
- Published
- 2015
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39. Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro.
- Author
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Casalena G, Krick S, Daehn I, Yu L, Ju W, Shi S, Tsai SY, D'Agati V, Lindenmeyer M, Cohen CD, Schlondorff D, and Bottinger EP
- Subjects
- Animals, Disease Models, Animal, Kidney Glomerulus metabolism, Kidney Glomerulus pathology, Mice, Mice, Transgenic, Mitochondria pathology, Nephritis pathology, Podocytes pathology, Proteinuria metabolism, Proteinuria pathology, Reactive Oxygen Species metabolism, Apoptosis physiology, Membrane Proteins metabolism, Mitochondria metabolism, Nephritis metabolism, Oxidative Stress physiology, Podocytes metabolism
- Abstract
Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA (mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17(+/+) wild-type (WT) and Mpv17(-/-) knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
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40. Absence of donor CD40 protects renal allograft epithelium and preserves renal function.
- Author
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Kraus AK, Cippá PE, Gaspert A, Chen J, Edenhofer I, Wüthrich RP, Lindenmeyer M, Segerer S, and Fehr T
- Subjects
- Animals, Apoptosis immunology, CD40 Antigens genetics, Dendritic Cells immunology, Epithelium immunology, Epithelium pathology, Kidney immunology, Kidney pathology, Kidney physiology, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, T-Lymphocytes, Cytotoxic immunology, Th17 Cells immunology, Transplantation, Homologous, CD40 Antigens deficiency, Kidney Transplantation, Tissue Donors
- Abstract
Blocking the CD40-CD154 pathway prevents allograft rejection and induces donor-specific tolerance in various experimental models. However, the translation to clinical studies has been hampered by unexpected thromboembolic complications of CD154-blocking antibodies. Thus, blocking CD40 instead is now considered as an alternative strategy. Here, we evaluated the role of donor CD40 in allospecific T-cell responses in vitro and in an in vivo model for renal transplantation. Fully MHC-mismatched allografts from CD40-deficient donors displayed better renal function than wild type. These functional data correlated with a lower level of apoptosis in renal tubular epithelial cells and higher expression of PD-L1, which is most probably because of a reduced Th17 response in recipients of a CD40-deficient donor. This hypothesis was supported in vitro, where donor CD40 expression was important for the induction of direct allospecific T-cell responses. Especially the induction of Th17 cells was critically dependent on donor CD40. IL-17A in conjunction with interferon-γ in turn rendered renal tubular epithelial cells to a more costimulatory state by upregulating CD40 and downregulating PD-L1 expression. In conclusion, CD40 blockade not only reduces the allospecific T-cell responses, but might also lead to protection of tubular epithelium from apoptosis and thereby preserve kidney allograft function., (© 2013 The Authors Transplant International © 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.)
- Published
- 2013
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41. Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury.
- Author
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Djudjaj S, Chatziantoniou C, Raffetseder U, Guerrot D, Dussaule JC, Boor P, Kerroch M, Hanssen L, Brandt S, Dittrich A, Ostendorf T, Floege J, Zhu C, Lindenmeyer M, Cohen CD, and Mertens PR
- Subjects
- Animals, Biopsy, Cell Line, Cell Proliferation, Disease Models, Animal, Female, Fibrosis, Humans, In Vitro Techniques, Intercellular Signaling Peptides and Proteins metabolism, Jagged-2 Protein, Kidney metabolism, Kidney pathology, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Nephritis, Interstitial metabolism, Nephritis, Interstitial pathology, Rats, Receptor, Notch1 physiology, Receptor, Notch3, Receptors, Notch deficiency, Receptors, Notch genetics, Signal Transduction physiology, Transforming Growth Factor beta pharmacology, Up-Regulation drug effects, Ureteral Obstruction metabolism, Ureteral Obstruction pathology, Inflammation physiopathology, Kidney physiopathology, Nephritis, Interstitial physiopathology, Receptors, Notch physiology, Ureteral Obstruction physiopathology
- Abstract
Kidney diseases impart a vast burden on affected individuals and the overall health care system. Progressive loss of renal parenchymal cells and functional decline following injury are often observed. Notch-1 and -2 receptors are crucially involved in nephron development and contribute to inflammatory kidney diseases. We specifically determined the participation of receptor Notch-3 following tubulointerstitial injury and in inflammatory responses. Here we show by heat map analyses that Notch-3 transcripts are up-regulated in human kidney diseases. A similar response was corroborated with kidney cells following TGF-β exposure in vitro. The murine unilateral ureteral obstruction (UUO) model mirrors hallmarks of tubulointerstitial injury and damage. A subset of tubular and interstitial cells demonstrated up-regulated Notch-3 receptor expression in diseased animals. We hypothesized a relevance of Notch-3 receptors for the chemotactic response. To address this question, animals with genetic ablation of receptor Notch-3 were analysed following UUO. As a result, we found that Notch-3-deficient animals are protected from tubular injury and cell loss with significantly reduced interstitial collagen deposition. Monocytic cell infiltration was significantly reduced and retarded, likely due to abrogated chemokine synthesis. A cell model was set up that mimics enhanced receptor Notch-3 expression and activation. Here a pro-mitogenic response was seen with activated signalling in tubular cells and fibroblasts. In conclusion, Notch-3 receptor fulfils non-redundant roles in the inflamed kidney that may not be replaced by other Notch receptor family members. Thus, specific blockade of this receptor may be suitable as therapeutic option to delay progression of kidney disease., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2012
- Full Text
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42. Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis.
- Author
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Berthier CC, Bethunaickan R, Gonzalez-Rivera T, Nair V, Ramanujam M, Zhang W, Bottinger EP, Segerer S, Lindenmeyer M, Cohen CD, Davidson A, and Kretzler M
- Subjects
- Animals, Gene Expression Profiling, Glomerulonephritis, IGA genetics, Glomerulonephritis, IGA immunology, Glomerulonephritis, IGA pathology, Humans, Inflammation genetics, Inflammation immunology, Inflammation pathology, Lupus Nephritis genetics, Male, Mice, Mice, Inbred NZB, Nephritis, Interstitial genetics, Nephritis, Interstitial immunology, Nephritis, Interstitial pathology, Proteinuria genetics, Proteinuria immunology, Proteinuria pathology, Crosses, Genetic, Disease Models, Animal, Gene Regulatory Networks immunology, Lupus Nephritis immunology, Lupus Nephritis pathology, Transcription, Genetic immunology
- Abstract
Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these preclinical models. In this study, we used an unbiased transcriptional network approach to define, in molecular terms, similarities and differences among three lupus models and human LN. Genome-wide gene-expression networks were generated using natural language processing and automated promoter analysis and compared across species via suboptimal graph matching. The three murine models and human LN share both common and unique features. The 20 commonly shared network nodes reflect the key pathologic processes of immune cell infiltration/activation, endothelial cell activation/injury, and tissue remodeling/fibrosis, with macrophage/dendritic cell activation as a dominant cross-species shared transcriptional pathway. The unique nodes reflect differences in numbers and types of infiltrating cells and degree of remodeling among the three mouse strains. To define mononuclear phagocyte-derived pathways in human LN, gene sets activated in isolated NZB/W renal mononuclear cells were compared with human LN kidney profiles. A tissue compartment-specific macrophage-activation pattern was seen, with NF-κB1 and PPARγ as major regulatory nodes in the tubulointerstitial and glomerular networks, respectively. Our study defines which pathologic processes in murine models of LN recapitulate the key transcriptional processes active in human LN and suggests that there are functional differences between mononuclear phagocytes infiltrating different renal microenvironments.
- Published
- 2012
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43. Resistance to ABT-737 in activated T lymphocytes: molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway.
- Author
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Cippà PE, Kraus AK, Lindenmeyer MT, Chen J, Guimezanes A, Bardwell PD, Wekerle T, Wüthrich RP, and Fehr T
- Subjects
- Animals, Bone Marrow Transplantation, Cyclosporine pharmacology, Graft vs Host Disease pathology, Mice, Mice, Inbred C57BL, Piperazines pharmacology, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Biphenyl Compounds pharmacology, Calcineurin metabolism, Drug Resistance physiology, NFATC Transcription Factors metabolism, Nitrophenols pharmacology, Signal Transduction drug effects, Sulfonamides pharmacology, T-Lymphocytes drug effects
- Abstract
Dynamic regulation of the intrinsic apoptosis pathway controls central and peripheral lymphocyte deletion, and may interfere with the pro-apoptotic potency of B-cell lymphoma 2 inhibitors such as ABT-737. By following a T-cell receptor (TCR) transgenic population of alloantigen-specific T cells, we found that sensitivity to ABT-737 radically changed during the course of allo-specific immune responses. Particularly, activated T cells were fully resistant to ABT-737 during the first days after antigen recognition. This phenomenon was caused by a TCR-calcineurin-nuclear factor of activated T cells-dependent upregulation of A1, and was therefore prevented by cyclosporine A (CsA). As a result, exposure to ABT-737 after alloantigen recognition induced selection of alloreactive T cells in vivo, whereas in combination with low-dose CsA, ABT-737 efficiently depleted alloreactive T cells in murine host-versus-graft and graft-versus-host models. Thus, ABT-737 resistance is not a prerogative of neoplastic cells, but it physiologically occurs in T cells after antigen recognition. Reversibility of this process by calcineurin inhibitors opens new pharmacological opportunities to modulate this process in the context of cancer, autoimmunity and transplantation.
- Published
- 2012
- Full Text
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44. The spectrum of podoplanin expression in encapsulating peritoneal sclerosis.
- Author
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Braun N, Alscher MD, Fritz P, Latus J, Edenhofer I, Reimold F, Alper SL, Kimmel M, Biegger D, Lindenmeyer M, Cohen CD, Wüthrich RP, and Segerer S
- Subjects
- Actins metabolism, Adult, Aged, Aged, 80 and over, Female, Fibroblasts metabolism, Fibroblasts pathology, Humans, Male, Membrane Glycoproteins genetics, Middle Aged, Muscle, Smooth metabolism, Muscle, Smooth pathology, Peritoneal Fibrosis etiology, Peritoneal Fibrosis genetics, Peritoneal Fibrosis pathology, Peritoneum pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Membrane Glycoproteins metabolism, Peritoneal Dialysis adverse effects, Peritoneal Fibrosis metabolism, Peritoneum metabolism
- Abstract
Encapsulating peritoneal sclerosis (EPS) is a life threatening complication of peritoneal dialysis (PD). Podoplanin is a glycoprotein expressed by mesothelial cells, lymphatic endothelial cells, and myofibroblasts in peritoneal biopsies from patients with EPS. To evaluate podoplanin as a marker of EPS we measured podoplanin mRNA and described the morphological patterns of podoplanin-positive cells in EPS. Included were 20 peritoneal biopsies from patients with the diagnosis of EPS (n = 5), patients on PD without signs of EPS (n = 5), and control patients (uremic patients not on PD, n = 5, non-uremic patients n = 5). EPS patient biopsies revealed significantly elevated levels of podoplanin mRNA (p<0.05). In 24 peritoneal biopsies from patients with EPS, podoplanin and smooth muscle actin (SMA) were localized by immunohistochemistry. Four patterns of podoplanin distribution were distinguishable. The most common pattern (8 of 24) consisted of organized, longitudinal layers of podoplanin-positive cells and vessels in the fibrotic zone ("organized" pattern). 7 of 24 biopsies demonstrated a diffuse distribution of podoplanin-positive cells, accompanied by occasional, dense clusters of podoplanin-positive cells. Five biopsies exhibited a mixed pattern, with some diffuse areas and some organized areas ("mixed"). These contained cuboidal podoplanin-positive cells within SMA-negative epithelial structures embedded in extracellular matrix. Less frequently observed was the complete absence of, or only focal accumulations of podoplanin-positive fibroblasts outside of lymphatic vessels (podoplanin "low", 4 of 24 biopsies). Patients in this group exhibited a lower index of systemic inflammation and a longer symptomatic period than in EPS patients with biopsies of the "mixed" type (p<0.05). In summary we confirm the increased expression of podoplanin in EPS, and distinguish EPS biopsies according to different podoplanin expression patterns which are associated with clinical parameters. Podoplanin might serve as a useful adjunct to the morphological workup of peritoneal biopsies.
- Published
- 2012
- Full Text
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45. Expression of the chemokine receptor CCR6 in human renal inflammation.
- Author
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Welsh-Bacic D, Lindenmeyer M, Cohen CD, Draganovici D, Mandelbaum J, Edenhofer I, Ziegler U, Regele H, Wüthrich RP, and Segerer S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Chemokine CCL20 genetics, Child, Child, Preschool, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Infant, Infant, Newborn, Male, Middle Aged, RNA, Messenger genetics, Receptors, CCR6 genetics, Reverse Transcriptase Polymerase Chain Reaction, Young Adult, Chemokine CCL20 metabolism, Glomerulonephritis metabolism, Glomerulonephritis, IGA metabolism, Inflammation metabolism, Kidney Failure, Chronic metabolism, Nephritis, Interstitial metabolism, Receptors, CCR6 metabolism
- Abstract
Background: Nodular inflammatory cell infiltrates with defined microarchitecture, i.e. tertiary lymphoid organs, develop in the tubulointerstitium during chronic renal inflammation. CCR6 and the corresponding ligand CCL20 are involved in the formation of gut-associated lymphatic tissue. We hypothesized that CCR6 might be involved in the formation of nodular infiltrates in the kidney., Methods: CCR6- and CD20-positive B cells were localized in renal biopsies with IgA nephropathy (n = 13), membranous nephropathy (n = 12), crescentic glomerulonephritis (cGN, n = 11) and chronic interstitial nephritis (n = 13), and in pre-implantation biopsies as controls (n = 8). The mRNA expression of CCR6 and the ligand CCL20 was quantified by real-time RT-PCR in 51 renal biopsies of the same disease entities., Results: In the pre-transplant biopsies, CCR6 was expressed by endothelial cells of peritubular and glomerular capillaries. In patients with glomerulonephritis, infiltrating cells were positive particularly in areas of nodular inflammatory cell accumulations. A major part of the CCR6-positive cells were CD20-positive B cells, but a part of the CD3-positive T cells were also found to be positive. The constitutive expression of CCR6 on the endothelium of glomerular capillaries was lost in biopsies with progressive injury. Tubular epithelial cells expressed CCR6 in inflamed kidneys, most commonly on the basolateral side., Conclusions: CCR6 and the corresponding ligand CCL20 might therefore be involved in the recruitment of T and B cells to organized nodular infiltrates in chronic renal inflammation. The functional role of endothelial CCR6 needs to be evaluated in further studies.
- Published
- 2011
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46. Dendritic cells in experimental renal inflammation--Part I.
- Author
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Lindenmeyer M, Noessner E, Nelson PJ, and Segerer S
- Subjects
- Animals, Humans, Mice, Dendritic Cells immunology, Disease Models, Animal, Kidney immunology, Kidney pathology, Nephritis immunology, Nephritis pathology
- Abstract
Dendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells that act as master regulators of acquired and innate immune responses. While descriptions of cells with dendritic morphology in rodent kidneys date back to the early 1970s, a network of DCs in the mouse kidney has only recently been described. DCs acquire distinct phenotypic and functional characteristics depending on the microenvironment and the disease stages. Concomitantly, their communication with cells of the adaptive immunity might have tissue-protective or tissue-deleterious consequences. This review summarizes results from recent studies on the role of DCs in experimental renal inflammation., (Copyright © 2011 S. Karger AG, Basel.)
- Published
- 2011
- Full Text
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47. Dendritic cells in human renal inflammation--Part II.
- Author
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Noessner E, Lindenmeyer M, Nelson PJ, and Segerer S
- Subjects
- Humans, Cytokines immunology, Dendritic Cells immunology, Kidney immunology, Kidney pathology, Nephritis immunology, Nephritis pathology
- Abstract
Dendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells that act as master regulators of acquired and innate immune responses. Here, we review the available information on their role in human renal inflammation. In the 1980s and early 1990s, major histocompatibility complex class II antigen- (HLA-DR) positive DCs were first described in normal human kidneys and in the interstitium of kidneys from patients with glomerulonephritis. Several DC subtypes were subsequently distinguished based on their expression of CD1c/BDCA-1, CD141/BDCA-3 and CD209/DC-SIGN (in combination with HLA-DR). These cells were almost exclusively found in the tubulointerstitium, with increased numbers seen during glomerulonephritis. It appears that the human renal tubulointerstitium harbors different DC types which allow the collection of both exogenous as well as endogenous antigens. Plasmacytoid DCs have a plasma cell-like morphology and were commonly found within nodular tubulointerstitial infiltrates. Follicular DCs are rarely seen, but show a predominant localization in organized infiltrates. CD207/langerin is a marker for Langerhans cells. Langerin-positive cells have been found in association with the collecting ducts and urothelium. A functional characterization of these subtypes has been hampered by the difficulty of obtaining samples for analysis. However, these studies are clearly required to define the role of DCs and DC subsets in the pathophysiology of renal disease., (Copyright © 2011 S. Karger AG, Basel.)
- Published
- 2011
- Full Text
- View/download PDF
48. Aerobic synthesis of vitamin B12: ring contraction and cobalt chelation.
- Author
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Heldt D, Lawrence AD, Lindenmeyer M, Deery E, Heathcote P, Rigby SE, and Warren MJ
- Subjects
- Aerobiosis, Bacterial Proteins metabolism, Chelating Agents, Models, Molecular, Oxygenases metabolism, Uroporphyrinogens metabolism, Vitamin B 12 chemistry, Cobalt metabolism, Vitamin B 12 biosynthesis
- Abstract
The aerobic biosynthetic pathway for vitamin B12 (cobalamin) biosynthesis is reviewed. Particular attention is focused on the ring contraction process, whereby an integral carbon atom of the tetrapyrrole-derived macrocycle is removed. Previous work had established that this chemically demanding step is facilitated by the action of a mono-oxygenase called CobG, which generates a hydroxy lactone intermediate. This mono-oxygenase contains both a non-haem iron and an Fe-S centre, but little information is known about its mechanism. Recent work has established that in bacteria such as Rhodobacter capsulatus, CobG is substituted by an isofunctional protein called CobZ. This protein has been shown to contain flavin, haem and Fe-S centres. A mechanism is proposed to explain the function of CobZ. Another interesting aspect of the aerobic cobalamin biosynthetic pathway is cobalt insertion, which displays some similarity to the process of magnesium chelation in chlorophyll synthesis. The genetic requirements of cobalt chelation and the subsequent reduction of the metal ion are discussed.
- Published
- 2005
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49. Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential.
- Author
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García-Piñeres AJ, Lindenmeyer MT, and Merfort I
- Subjects
- Animals, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, HeLa Cells, Humans, I-kappa B Kinase, Jurkat Cells, Macrophages, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Mice, Mutation, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors, Synaptotagmin I, Synaptotagmins, Transcription Factor RelA, Transfection, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Calcium-Binding Proteins, Cysteine, DNA-Binding Proteins antagonists & inhibitors, Ethylmaleimide pharmacology, NF-kappa B antagonists & inhibitors, NF-kappa B genetics, NF-kappa B metabolism, Sesquiterpenes pharmacology, Transcriptional Activation drug effects
- Abstract
Sesquiterpene lactones (SLs) are potent anti-inflammatory substances. It was previously shown that the anti-inflammatory effect could be partly explained by the inhibition of the transcription factor NF-kappaB. Whether they inhibit the DNA binding of NF-kappaB, the activation of the IkappaB-kinase, or both is still a matter of debate. The data supporting these hypotheses were obtained using different cell systems. In this contribution we analyzed the mechanism of the sesquiterpene lactone-mediated inhibition using different cell systems, and showed that in all the cell lines analyzed, SLs inhibited both NF-kappaB binding and the IkappaB-kinase, but that the former played a more preponderant role in the inhibition. These results again confirm the importance of cysteine 38 in the inhibition and regulation of NF-kappaB's function. Moreover, we compared the selectivity of the SL parthenolide with that of N-ethyl maleimide (NEM). We showed that NEM directly alkylated p65 as well as p50 of NF-kappaB, whereas SLs possess a selectivity towards p65. Finally, we studied the transactivating properties of various p65 mutants, to analyze the effect of exchanged cysteine residues in the DNA binding domain of NF-kappaB/p65 on its function and demonstrated that the transactivating potential of the mutants did not correlate with their DNA binding strenght., (Copyright 2004 Elsevier Inc.)
- Published
- 2004
- Full Text
- View/download PDF
50. Regulation of Pseudomonas aeruginosa hemF and hemN by the dual action of the redox response regulators Anr and Dnr.
- Author
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Rompf A, Hungerer C, Hoffmann T, Lindenmeyer M, Römling U, Gross U, Doss MO, Arai H, Igarashi Y, and Jahn D
- Subjects
- Aerobiosis, Amino Acid Sequence, Anaerobiosis, Bacterial Proteins genetics, Base Sequence, Chromosome Mapping, Cloning, Molecular, Coproporphyrinogens metabolism, DNA Primers genetics, DNA, Bacterial genetics, Gene Expression Regulation, Bacterial, Genes, Bacterial, Molecular Sequence Data, Mutation, Oxidation-Reduction, Pseudomonas aeruginosa genetics, Pseudomonas aeruginosa growth & development, RNA, Bacterial genetics, RNA, Bacterial metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Bacterial Proteins metabolism, Coproporphyrinogen Oxidase, DNA-Binding Proteins, Pseudomonas aeruginosa metabolism, Trans-Activators, Transcription Factors metabolism
- Abstract
The oxidative decarboxylation of coproporphyrinogen III catalysed by an oxygen-dependent oxidase (HemF) and an oxygen-independent dehydrogenase (HemN) is one of the key regulatory points of haem biosynthesis in Pseudomonas aeruginosa. To investigate the oxygen-dependent regulation of hemF and hemN, the corresponding genes were cloned from the P. aeruginosa chromosome. Recognition sequences for the Fnr-type transcriptional regulator Anr were detected -44.5 bp from the 5' end of the hemF mRNA transcript and at an optimal distance of -41.5 bp with respect to the transcriptional start of hemN. An approximately 10-fold anaerobic induction of hemN gene expression was mediated by the dual action of Anr and a second Fnr-type regulator, Dnr. Regulation by both proteins required the Anr recognition sequence. Surprisingly, aerobic expression of hemN was dependent only on Anr. An anr mutant did not contain detectable amounts of hemN mRNA and accumulated coproporphyrin III both aerobically and anaerobically, indicating the importance of HemN for aerobic and anaerobic haem formation. Mutation of hemN and hemF did not abolish aerobic or anaerobic growth, indicating the existence of an additional HemN-type enzyme, which was termed HemZ. Expression of hemF was induced approximately 20-fold during anaerobic growth and, as was found for hemN, both Anr and Dnr were required for anaerobic induction. Paradoxically, oxygen is necessary for HemF catalysis, suggesting the existence of an additional physiological function for the P. aeruginosa HemF protein.
- Published
- 1998
- Full Text
- View/download PDF
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