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793 results on '"Humphreys, Benjamin D."'

5. Adamts12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts

Author

Hoeft, Konrad, Koch, Lars, Ziegler, Susanne, Zhang, Ling, Luetke, Steffen, Tanzer, Maria C., Mohanta, Debashish, Schumacher, David, Schreibing, Felix, Long, Qingqing, Kim, Hyojin, Klinkhammer, Barbara M., Schikarski, Carla, Maryam, Sidrah, Baens, Mathijs, Hermann, Juliane, Krieg, Sarah, Peisker, Fabian, De Laporte, Laura, Schaefer, Gideon J.L., Menzel, Sylvia, Jankowski, Joachim, Humphreys, Benjamin D., Wahida, Adam, Schneider, Rebekka K., Versele, Matthias, Boor, Peter, Mann, Matthias, Sengle, Gerhard, Hayat, Sikander, and Kramann, Rafael

Subjects
Medical research, Medicine, Experimental, Fibrosis -- Physiological aspects, Proteases -- Physiological aspects, Extracellular matrix -- Physiological aspects, Fibroblasts -- Physiological aspects -- Health aspects, Wounds and injuries -- Physiological aspects
Abstract

Fibrosis represents the uncontrolled replacement of parenchymal tissue with extracellular matrix (ECM) produced by myofibroblasts. While genetic fate-tracing and single-cell RNA-Seq technologies have helped elucidate fibroblast heterogeneity and ontogeny beyond fibroblast to myofibroblast differentiation, newly identified fibroblast populations remain ill defined, with respect to both the molecular cues driving their differentiation and their subsequent role in fibrosis. Using an unbiased approach, we identified the metalloprotease ADAMTS12 as a fibroblast-specific gene that is strongly upregulated during active fibrogenesis in humans and mice. Functional in vivo KO studies in mice confirmed that Adamts12 was critical during fibrogenesis in both heart and kidney. Mechanistically, using a combination of spatial transcriptomics and expression of catalytically active or inactive ADAMTS12, we demonstrated that the active protease of ADAMTS12 shaped ECM composition and cleaved hemicentin 1 (HMCN1) to enable the activation and migration of a distinct injury- responsive fibroblast subset defined by aberrant high JAK/STAT signaling., Introduction Fibrosis represents the uncontrolled replacement of parenchymal tissue by extracellular matrix (ECM) (1). Whereas deposition of ECM sustains tissue integrity immediately after injury, continued deposition of ECM by myofibroblasts [...]

Published
2024
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7. A genetically inducible endothelial niche enables vascularization of human kidney organoids with multilineage maturation and emergence of renin expressing cells

Author

Maggiore, Joseph C., LeGraw, Ryan, Przepiorski, Aneta, Velazquez, Jeremy, Chaney, Christopher, Vanichapol, Thitinee, Streeter, Evan, Almuallim, Zainab, Oda, Akira, Chiba, Takuto, Silva-Barbosa, Anne, Franks, Jonathan, Hislop, Joshua, Hill, Alex, Wu, Haojia, Pfister, Katherine, Howden, Sara E., Watkins, Simon C., Little, Melissa H., Humphreys, Benjamin D., Kiani, Samira, Watson, Alan, Stolz, Donna B., Davidson, Alan J., Carroll, Tom, Cleaver, Ondine, Sims-Lucas, Sunder, Ebrahimkhani, Mo R., and Hukriede, Neil A.

Published
2024
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9. Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma

Author

Wu, Yige, Terekhanova, Nadezhda V., Caravan, Wagma, Naser Al Deen, Nataly, Lal, Preet, Chen, Siqi, Mo, Chia-Kuei, Cao, Song, Li, Yize, Karpova, Alla, Liu, Ruiyang, Zhao, Yanyan, Shinkle, Andrew, Strunilin, Ilya, Weimholt, Cody, Sato, Kazuhito, Yao, Lijun, Serasanambati, Mamatha, Yang, Xiaolu, Wyczalkowski, Matthew, Zhu, Houxiang, Zhou, Daniel Cui, Jayasinghe, Reyka G., Mendez, Daniel, Wendl, Michael C., Clark, David, Newton, Chelsea, Ruan, Yijun, Reimers, Melissa A., Pachynski, Russell K., Kinsinger, Chris, Jewell, Scott, Chan, Daniel W., Zhang, Hui, Chaudhuri, Aadel A., Chheda, Milan G., Humphreys, Benjamin D., Mesri, Mehdi, Rodriguez, Henry, Hsieh, James J., Ding, Li, and Chen, Feng

Published
2023
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10. Author Correction: Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma

Author

Wu, Yige, Terekhanova, Nadezhda V., Caravan, Wagma, Naser Al Deen, Nataly, Lal, Preet, Chen, Siqi, Mo, Chia-Kuei, Cao, Song, Li, Yize, Karpova, Alla, Liu, Ruiyang, Zhao, Yanyan, Shinkle, Andrew, Strunilin, Ilya, Weimholt, Cody, Sato, Kazuhito, Yao, Lijun, Serasanambati, Mamatha, Yang, Xiaolu, Wyczalkowski, Matthew, Zhu, Houxiang, Zhou, Daniel Cui, Jayasinghe, Reyka G., Mendez, Daniel, Wendl, Michael C., Clark, David, Newton, Chelsea, Ruan, Yijun, Reimers, Melissa A., Pachynski, Russell K., Kinsinger, Chris, Jewell, Scott, Chan, Daniel W., Zhang, Hui, Chaudhuri, Aadel A., Chheda, Milan G., Humphreys, Benjamin D., Mesri, Mehdi, Rodriguez, Henry, Hsieh, James J., Ding, Li, and Chen, Feng

Published
2023
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14. Targeting de novo lipogenesis to mitigate kidney disease

Author

Li, Haikuo and Humphreys, Benjamin D.

Subjects
Medical research -- Physiological aspects, Medicine, Experimental -- Physiological aspects, Genes -- Physiological aspects, Chronic kidney failure -- Development and progression, Ligases -- Physiological aspects, Health care industry
Abstract

Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While dysregulated lipid metabolism is one hallmark of CKD, the pathogenesis of cellular lipid accumulation remains unclear. In this issue of theJCI, Mukhi et al. Identify acyl-CoA synthetase short-chain family 2 (ACSS2) as a disease risk gene and demonstrate a role for ACSS2 in de novo lipogenesis (DNL). Notably, genetic or pharmacological inhibition of DNL protected against kidney disease progression in mice. These findings warrant evaluation of DNL inhibition with respect to efficacy and safety in people with CKD., Identification of ACSS2 with computational genomics Chronic kidney disease (CKD) is a major global health burden, resulting in 1.2 million deaths and 28.0 million years of life lost annually (1, [...]

Published
2024
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16. Circulating testican-2 is a podocyte-derived marker of kidney health

Author

Ngo, Debby, Wen, Donghai, Gao, Yan, Keyes, Michelle J, Drury, Erika R, Katz, Dan H, Benson, Mark D, Sinha, Sumita, Shen, Dongxiao, Farrell, Laurie A, Peterson, Bennet D, Friedman, David J, Elmariah, Sammy, Young, Bessie A, Smith, J Gustav, Yang, Qiong, Vasan, Ramachandran S, Larson, Martin G, Correa, Adolfo, Humphreys, Benjamin D, Wang, Thomas J, Pollak, Martin R, Wilson, James G, Gerszten, Robert E, and Rhee, Eugene P

Subjects
Kidney Disease, Clinical Research, Underpinning research, 1.1 Normal biological development and functioning, Renal and urogenital, Cardiovascular, Black or African American, Aptamers, Peptide, Biomarkers, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney, Kidney Function Tests, Kidney Glomerulus, Male, Middle Aged, Podocytes, Proteoglycans, Proteomics, testican-2, proteomics, chronic kidney disease
Abstract

In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.

Published
2020

22. Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies.

Author

Morris, Andrew P, Le, Thu H, Wu, Haojia, Akbarov, Artur, van der Most, Peter J, Hemani, Gibran, Smith, George Davey, Mahajan, Anubha, Gaulton, Kyle J, Nadkarni, Girish N, Valladares-Salgado, Adan, Wacher-Rodarte, Niels, Mychaleckyj, Josyf C, Dueker, Nicole D, Guo, Xiuqing, Hai, Yang, Haessler, Jeffrey, Kamatani, Yoichiro, Stilp, Adrienne M, Zhu, Gu, Cook, James P, Ärnlöv, Johan, Blanton, Susan H, de Borst, Martin H, Bottinger, Erwin P, Buchanan, Thomas A, Cechova, Sylvia, Charchar, Fadi J, Chu, Pei-Lun, Damman, Jeffrey, Eales, James, Gharavi, Ali G, Giedraitis, Vilmantas, Heath, Andrew C, Ipp, Eli, Kiryluk, Krzysztof, Kramer, Holly J, Kubo, Michiaki, Larsson, Anders, Lindgren, Cecilia M, Lu, Yingchang, Madden, Pamela AF, Montgomery, Grant W, Papanicolaou, George J, Raffel, Leslie J, Sacco, Ralph L, Sanchez, Elena, Stark, Holger, Sundstrom, Johan, Taylor, Kent D, Xiang, Anny H, Zivkovic, Aleksandra, Lind, Lars, Ingelsson, Erik, Martin, Nicholas G, Whitfield, John B, Cai, Jianwen, Laurie, Cathy C, Okada, Yukinori, Matsuda, Koichi, Kooperberg, Charles, Chen, Yii-Der Ida, Rundek, Tatjana, Rich, Stephen S, Loos, Ruth JF, Parra, Esteban J, Cruz, Miguel, Rotter, Jerome I, Snieder, Harold, Tomaszewski, Maciej, Humphreys, Benjamin D, and Franceschini, Nora

Subjects
Kidney, Humans, Kidney Calculi, Hypertension, Histones, Glomerular Filtration Rate, Histone Code, Blood Pressure, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Ethnic Groups, Female, Male, Renal Insufficiency, Chronic, Genome-Wide Association Study, Genetic Loci, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic
Abstract

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

Published
2019

31. Super chickens, givers, and collective intelligence: the importance of collaboration, teamwork, and mentorship in science.

Author

Humphreys, Benjamin D.

Subjects
*SWARM intelligence, *MENTORING, *SCIENTIFIC literature, *CHICKENS, *ORGANIZATIONAL behavior
Abstract

The article focuses on the value of scientific collaborations in advancing research, drawing a comparison to the unique opportunities offered by events like the Joint Meeting. Topics include the importance of collaboration in scientific progress, a personal reflection on the impact of Leonard Adleman's work on molecular computation, and the concept of using DNA to solve complex computational problems such as the Hamiltonian Path.

Published
2024
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32. Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution.

Author

Yoshiharu Muto, Yasuhiro Yoshimura, Haojia Wu, Chang-Panesso, Monica, Ledru, Nicolas, Woodward, Owen M., Outeda, Patricia, Tao Cheng, Mahjoub, Moe R., Watnick, Terry J., and Humphreys, Benjamin D.

Subjects
POLYCYSTIC kidney disease, KIDNEY failure, REGULATOR genes, GENETIC disorders, GENETIC transcription regulation
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single-nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Pik3c3 expression profiling in the mouse kidney and its role in proximal tubule cell physiology.

Author

Ting Liu, Jialing Yuan, Caihong Dai, Chen, Mystie X., Fan, Jerry, Humphreys, Benjamin D., Fulton, David J. R., Kleven, Daniel T., Xingjun Fan, Zheng Dong, and Jian-Kang Chen

Subjects
EPIDERMAL growth factor receptors, PHOSPHATIDYLINOSITOL 3-kinases, KIDNEY tubules, PROXIMAL kidney tubules, CELL physiology, INTERSTITIAL cells
Abstract

The class 3 phosphatidylinositol 3-kinase (Pik3c3) plays critical roles in regulating autophagy, endocytosis, and nutrient sensing, but its expression profile in the kidney remains undefined. Recently, we validated a Pik3c3 antibody through immunofluorescence staining of kidney tissues from cell type-specific Pik3c3 knockout mice. Immunohistochemistry unveiled significant disparities in Pik3c3 expression levels across various kidney cell types. Notably, renal interstitial cells exhibit minimal Pik3c3 expression. Further, coimmunofluorescence staining, utilizing nephron segment- or cell type-specific markers, revealed nearly undetectable levels of Pik3c3 expression in glomerular mesangial cells and endothelial cells. Intriguingly, although podocytes exhibit the highest Pik3c3 expression levels among all kidney cell types, the renal proximal tubule cells (RPTCs) express the highest level of Pik3c3 among all renal tubules. RPTCs are known to express the highest level of the epidermal growth factor receptor (EGFR) in adult kidneys; however, the role of Pik3c3 in EGFR signaling within RPTCs remains unexplored. Therefore, we conducted additional cell culture studies. The results demonstrated that Pik3c3 inhibition significantly delayed EGF-stimulated EGFR degradation and the termination of EGFR signaling in RPTCs. Mechanistically, Pik3c3 inhibition surprisingly did not affect the initial endocytosis process but instead impeded the lysosomal degradation of EGFR. In summary, this study defines, for the first time, the expression profile of Pik3c3 in the mouse kidney and also highlights a pivotal role of Pik3c3 in the proximal tubule cells. These findings shed light on the intricate mechanisms underlying Pik3c3-mediated regulation of EGFR signaling, providing valuable insights into the role of Pik3c3 in renal cell physiology. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Reduced guanidinoacetate in plasma of patients with autosomal dominant Fanconi syndrome due to heterozygous P341L GATM variant and study of organoids towards treatment.

Author

Portales‐Castillo, Ignacio, Singal, Rhea, Ambrose, Anastasia, Song, Jong Hee, Son, Minsoo, Goo, Young Ah., Zhou, Wen, Traum, Avram Z., Coler‐Reilly, Ariella, Humphreys, Benjamin D., Civitelli, Roberto, Jüppner, Harald, Lundquist, Andrew L., Seres, Peter, Allegretti, Andrew S., and Mercimek‐Andrews, Saadet

Published
2024
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37. Tubular CPT1A deletion minimally affects aging and chronic kidney injury

Author

Hammoud, Safaa, primary, Ivanova, Alla, additional, Osaki, Yosuke, additional, Funk, Steven, additional, Yang, Haichun, additional, Viquez, Olga, additional, Delgado, Rachel, additional, Lu, Dongliang, additional, Phillips Mignemi, Melanie, additional, Tonello, Jane, additional, Colon, Selene, additional, Lantier, Louise, additional, Wasserman, David H., additional, Humphreys, Benjamin D., additional, Koenitzer, Jeffrey, additional, Kern, Justin, additional, de Caestecker, Mark, additional, Finkel, Toren, additional, Fogo, Agnes, additional, Messias, Nidia, additional, Lodhi, Irfan J., additional, and Gewin, Leslie S., additional

Published
2024
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40. Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis

Author

Knight, Richard, Lecker, Stewart H., Stillman, Isaac, Bogen, Steve, Amodu, Afolarin A., Ilori, Titlayo, Maikhor, Shana, Schmidt, Insa M., Beck, Laurence H., Henderson, Joel M., Onul, Ingrid, Verma, Ashish, McMahon, Gearoid M., Valerius, M. Todd, Waikar, Sushrut, Weins, Astrid, Colona, Mia R., Greka, Anna, Hacohen, Nir, Hoover, Paul J., Marshall, Jamie L., Aulisio, Mark, Chen, Yijiang M., Janowczyk, Andrew, Jayapandian, Catherine, Viswanathan, Vidya S., Bush, William S., Crawford, Dana C., Madabhushi, Anant, Bush, Lakeshia, Cooperman, Leslie, Gonzalez-Vicente, Agustin, Herlitz, Leal, Jolly, Stacey, Nguyen, Jane, O’toole, John, Palmer, Ellen, Poggio, Emilio, Sedor, John, Sendrey, Dianna, Spates-Harden, Kassandra, Taliercio, Jonathan, Bjornstad, Petter M., Pyle, Laura, Vinovskis, Carissa, Appelbaum, Paul, Balderes, Olivia, Barasch, Jonathan M., Bomback, Andrew S., Canetta, Pietro A., D’Agati, Vivette D., Kiryluk, Krzysztof, Kudose, Satoru, Mehl, Karla, Shang, Ning, Bansal, Shweta, Alexandrov, Theodore, Rennke, Helmut, El-Achkar, Tarek M., Barwinska, Daria, Bledso, Sharon, Borner, Katy, Bueckle, Andreas, Cheng, Yinghua, Dagher, Pierre C., Dunn, Kenneth W., Eadon, Michael T., Ferkowicz, Michael J., Herr, Bruce W., Kelly, Katherine J., Ferreira, Ricardo Melo, Quardokus, Ellen M., Record, Elizabeth, Rivera, Marcelino, Su, Jing, Sutton, Timothy A., Williams, James C., Jr., Winfree, Seth, Jain, Yashvardhan, Menez, Steven, Parikh, Chirag R., Rosenberg, Avi, Corona-Villalobos, Celia P., Wen, Yumeng, Johansen, Camille, Rosas, Sylvia E., Roy, Neil, Sun, Jennifer, Williams, Mark, Azeloglu, Evren U., Hansen, Jens, He, Cijang, Iyengar, Ravi, Xiong, Yuguang, Prasad, Pottumarthi, Srivastava, Anand, Madhavan, Sethu M., Parikh, Samir, Rovin, Brad, Shapiro, John P., Anderton, Christopher R., Lukowski, Jessica, Pasa-Tolic, Ljiljana, Velickovic, Dusan, Oliver, George (Holt), Ardayfio, Joseph, Bebiak, Jack, Brown, Keith, Campbell, Taneisha, Campbell, Catherine E., Hayashi, Lynda, Jefferson, Nichole, Roberts, Glenda V., Saul, John, Shpigel, Anna, Stutzke, Christy, Koewler, Robert, Pinkeney, Roy, Sealfon, Rachel, Troyanskaya, Olga, Wong, Aaron, Tuttle, Katherine R., Pollack, Ari, Goltsev, Yury, Ginley, Brandon, Lucarelli, Nicholas, Lutnick, Brendon, Sarder, Pinaki, Lake, Blue B., Zhang, Kun, Boada, Patrick, Laszik, Zoltan G., Nolan, Garry, Anjani, Kavya, Sarwal, Minnie, Mukatash, Tariq, Sigdel, Tara, Alloway, Rita R., Burg, Ashley R., Lee, Paul J., Rike, Adele, Shi, Tiffany, Woodle, E. Steve, Ascani, Heather, Balis, Ulysses G.J., Blanc, Victoria M., Conser, Ninive C., Eddy, Sean, Frey, Renee, He, Yougqun, Hodgin, Jeffrey B., Kretzler, Matthias, Lienczewski, Chrysta, Luo, Jinghui, Mariani, Laura H., Menon, Rajasree, Otto, Edgar, Schaub, Jennifer, Steck, Becky, Elder, Michele M., Gilliam, Matthew, Hall, Daniel E., Murugan, Raghavan, Palevsky, Paul M., Randhawa, Parmjeet, Rosengart, Matthew, Tublin, Mitchell, Vita, Tina, Winters, James, Kellum, John A., Alpers, Charles E., Berglund, Ashley, Berry, Brooke, Blank, Kristina N., Carson, Jonas, Daniel, Stephen, De Boer, Ian H., Dighe, Ashveena L., Dowd, Frederick, Grewenow, Stephanie M., Himmelfarb, Jonathan, Hoofnagle, Andrew N., Limonte, Christine, McClelland, Robyn L., Mooney, Sean D., Rezaei, Kasra, Shankland, Stuart, Snyder, Jamie, Wang, Ruikang, Wilcox, Adam, Williams, Kayleen, Park, Christopher, Montellano, Richard, Pamreddy, Annapurna, Sharma, Kumar, Venkatachalam, Manjeri, Ye, Hongping, Zhang, Guanshi, Basit, Mujeeb, Hedayati, S. Susan, Kermani, Asra, Lee, Simon C., Lu, Christopher Y., Miller, R. Tyler, Moe, Orson W., Patel, Jiten, Pillai, Anil, Sambandam, Kamalanathan, Torrealba, Jose, Toto, Robert D., Vazquez, Miguel, Wang, Nancy, Wen, Natasha, Zhang, Dianbo, Park, Harold, Caprioli, Richard M., Patterson, Nathan, Sharman, Kavya, Spraggins, Jeffrey M., Van de Plas, Raf, Basta, Jeanine, Diettman, Sabine M., Gaut, Joseph P., Jain, Sanjay, Rauchman, Michael I., Vijayan, Anitha, Cantley, Lloyd G., Kakade, Vijaykumar R., Moledina, Dennis, Shaw, Melissa M., Ugwuowo, Ugochukwu, Wilson, Francis P., Arora, Tanima, Kestenbaum, Bryan R., Alexopoulos, Leonidas G., Palsson, Ragnar, Liu, Jing, Stillman, Isaac E., Rennke, Helmut G., Vaidya, Vishal S., Wu, Haojia, Humphreys, Benjamin D., and Waikar, Sushrut S.

Published
2021
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43. Decoupling dedifferentiation and [G.sup.2]/M arrest in kidney fibrosis

Author

Humphreys, Benjamin D.

Subjects
Health care industry
Abstract

Understanding the cellular mechanisms underlying chronic kidney disease (CKD) progression is required to develop effective therapeutic approaches. In this issue of the JCI, Taguchi, Elias, et al. explore the relationship between cyclin G1 (CG1), an atypical cyclin that induces [G.sup.2]/M proximal tubule cell cycle arrest, and epithelial dedifferentiation during fibrogenesis. While CG1-knockout mice were protected from fibrosis and had reduced [G.sup.2]/M arrest, protection was unexpectedly independent of induction of [G.sup.2]/M arrest. Rather, CG1 drove fibrosis by regulating maladaptive dedifferentiation in a CDK5-dependent mechanism. These findings highlight the importance of maladaptive epithelial dedifferentiation in kidney fibrogenesis and identify CG1/CDK5 signaling as a therapeutic target in CKD progression., The proximal tubule in the AKI-to-CKD transition Chronic kidney disease (CKD) affects approximately 800 million people worldwide and treatment options are limited (1). CKD is characterized by tubular atrophy, inflammation, [...]

Published
2022
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46. Clinical Use of the Urine Biomarker [TIMP-2] × [IGFBP7] for Acute Kidney Injury Risk Assessment

Author

Vijayan, Anitha, Faubel, Sarah, Askenazi, David J, Cerda, Jorge, Fissell, William H, Heung, Michael, Humphreys, Benjamin D, Koyner, Jay L, Liu, Kathleen D, Mour, Girish, Nolin, Thomas D, Bihorac, Azra, Group, American Society of Nephrology Acute Kidney Injury Advisory, Basu, Rajit K, Bhatt, Udayan Y, Connor, Michael J, Davidson, Alan J, de Caestecker, Mark P, Doi, Kent, Golestaneh, Ladan, Mour, Girish K, Singh, Prabhleen, and Thakar, Charuhas V

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Prevention, Kidney Disease, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Renal and urogenital, Acute Kidney Injury, Biomarkers, Clinical Trials as Topic, Decision Trees, Early Diagnosis, Humans, Insulin-Like Growth Factor Binding Proteins, Risk Assessment, Tissue Inhibitor of Metalloproteinase-2, Acute kidney injury, biomarker, [TIMP-2] x [IGFBP7], diagnosis, critically ill, tissue inhibitor of metalloproteinase 2, insulin-like growth factor binding protein 7, NephroCheck, early detection, risk assessment, renal dysfunction, decreased kidney function, American Society of Nephrology Acute Kidney Injury Advisory Group, [TIMP-2] × [IGFBP7], Public Health and Health Services, Urology & Nephrology, Clinical sciences
Abstract

Acute kidney injury (AKI) is a serious complication, commonly occurring in the critically ill population, with devastating short- and long-term consequences. Despite standardization of the definition and staging of AKI, early recognition remains challenging given that serum creatinine level is a marker, albeit imperfect, of kidney function and not kidney injury. Furthermore, the delay in increase in serum creatinine level after loss of glomerular filtration also prevents timely detection of decreased kidney function in patients with AKI. During the past decade, numerous clinical investigations have evaluated the utility of several biomarkers in the early diagnosis and risk stratification of AKI. In 2014, the US Food and Drug Administration approved the marketing of a test based on the combination of urine concentrations of tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 ([TIMP-2] × [IGFBP7]) to determine whether certain critically ill patients are at risk for developing moderate to severe AKI. The optimal role of this biomarker in the diagnosis, management, and prognosis of AKI in different clinical settings requires further clarification. In this perspective, we summarize the biological actions of these 2 cell-cycle arrest biomarkers and present important considerations regarding the clinical application, interpretation, and limitations of this novel test for the early detection of AKI.

Published
2016

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