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Crescentic glomerulonephritis (GN) is the most severe form of GN and is associated with significant morbidity and mortality despite aggressive immunotherapy with steroids, cytotoxic drugs, and plasmapheresis. We examined the therapeutic efficacy of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG, 50 mg/kg BW/day x3 weeks), a potent anti-inflammatory and anti-oxidant agent, on experimental crescentic GN induced in 129/svJ mice by administration of rabbit anti-mouse glomerular basement membrane sera. Routine histology and key molecules involved in inflammatory and redox signaling were studied. EGCG treatment significantly reduced mortality, decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. The improvements in renal function and histology were accompanied by the restoration of Nrf2 signaling (which was impaired in vehicle-treated mice) as shown by increased nuclear translocation of Nrf2 and cytoplasmic glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione peroxidase. EGCG-treated mice also showed reduction in p-Akt, p-JNK, p-ERK1/2 and p-P38 as well as restoration of PPARγ and SIRT1 levels. Lower dose of EGCG (25 mg/kg BW/day x2 weeks) treatment also significantly decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. Thus, our data illustrate the efficacy of EGCG in reversing the progression of crescentic GN in mice by targeting multiple signaling and inflammatory pathways as well as countering oxidative stress.

Crescentic glomerulonephritis (GN) is the most severe form of GN and is associated with significant morbidity and mortality despite aggressive immunotherapy with steroids, cytotoxic drugs, and plasmapheresis. We examined the therapeutic efficacy of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG, 50 mg/kg BW/day x3 weeks), a potent anti-inflammatory and anti-oxidant agent, on experimental crescentic GN induced in 129/svJ mice by administration of rabbit anti-mouse glomerular basement membrane sera. Routine histology and key molecules involved in inflammatory and redox signaling were studied. EGCG treatment significantly reduced mortality, decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. The improvements in renal function and histology were accompanied by the restoration of Nrf2 signaling (which was impaired in vehicle-treated mice) as shown by increased nuclear translocation of Nrf2 and cytoplasmic glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione peroxidase. EGCG-treated mice also showed reduction in p-Akt, p-JNK, p-ERK1/2 and p-P38 as well as restoration of PPARγ and SIRT1 levels. Lower dose of EGCG (25 mg/kg BW/day x2 weeks) treatment also significantly decreased proteinuria and serum creatinine, and markedly improved renal histology when compared with vehicle-treated mice. Thus, our data illustrate the efficacy of EGCG in reversing the progression of crescentic GN in mice by targeting multiple signaling and inflammatory pathways as well as countering oxidative stress.

Administration of intravenous iron to supplement erythropoiesis stimulating agents (ESAs) has become a common practice in the management of anemia in patients with end-stage renal disease. Randomized clinical trials of anemia correction in this population have shown more adverse outcomes in CKD and ESRD patients assigned to the higher hemoglobin targets. Retrospective analysis of these trials suggests that morbidity is higher in subjects who fail to achieve the designated hemoglobin target and are typically exposed to higher doses of ESAs and iron than those that easily achieve the intended targets. Intravenous iron administration circumvents the natural biologic mechanisms for handling and utilization of iron. There is in vitro and in vivo evidence that intravenous iron preparations can cause oxidative stress, endothelial dysfunction, inflammation, impaired immunity, and renal injury. Since iron overload is known to promote endothelial dysfunction, cardiovascular disease, and immune dysfunction which are the leading causes of premature mortality in CKD and ESRD patients, it is imperative to exercise caution with the use of IV iron preparations in this population. The present review is intended to provide a brief overview of the potential adverse effects of the overzealous use of these agents.

BackgroundDysregulaiton of phosphate homeostasis as occurs in chronic kidney disease is associated with cardiovascular complications. It has been suggested that both hyperphosphatemia and hypophosphatemia can cause cardiovascular disease. The molecular mechanisms by which high or low serum phosphate levels adversely affect cardiovascular function are poorly understood. The purpose of this study was to explore the mechanisms of endothelial dysfunction in the presence of non-physiologic phosphate levels.Methodology/Principal FindingsWe studied the effects of simulated hyper- and hypophosphatemia in human umbilical vein endothelial cells in vitro. We found both simulated hyperphosphatemia and hypophosphatemia decrease eNOS expression and NO production. This was associated with reduced intracellular calcium, increased protein kinase C β2 (PKCβ2), reduced cell viability, and increased apoptosis. While simulated hyperphosphatemia was associated with decreased Akt/p-Akt, Bcl-xl/Bax ratios, NFkB-p65 and p-Erk abundance, simulated hypophosphatemia was associated with increased Akt/p-Akt and Bcl-xl/Bax ratios and p-Mek, p38, and p-p38 abundance.Conclusions/SignificanceThis is the first demonstration of endothelial dysfunction with hypophosphatemia. Our data suggests that both hyperphosphatemia and hypophosphatemia decrease eNOS activity via reduced intracellular calcium and increased PKCβ2. Hyperphosphatemia also appears to reduce eNOS transcription via reduced signaling through PI3K/Akt/NF-kB and MAPK/NF-kB pathways. On the other hand, hypophosphatemia appears to activate these pathways. Our data provides the basis for further studies to elucidate the relationship between altered phosphate homeostasis and cardiovascular disease. As a corollary, our data suggests that the level of phosphate in the culture media, if not in the physiologic range, may inadvertently affect experimental results.

Administration of intravenous iron to supplement erythropoiesis stimulating agents (ESAs) has become a common practice in the management of anemia in patients with end-stage renal disease. Randomized clinical trials of anemia correction in this population have shown more adverse outcomes in CKD and ESRD patients assigned to the higher hemoglobin targets. Retrospective analysis of these trials suggests that morbidity is higher in subjects who fail to achieve the designated hemoglobin target and are typically exposed to higher doses of ESAs and iron than those that easily achieve the intended targets. Intravenous iron administration circumvents the natural biologic mechanisms for handling and utilization of iron. There is in vitro and in vivo evidence that intravenous iron preparations can cause oxidative stress, endothelial dysfunction, inflammation, impaired immunity, and renal injury. Since iron overload is known to promote endothelial dysfunction, cardiovascular disease, and immune dysfunction which are the leading causes of premature mortality in CKD and ESRD patients, it is imperative to exercise caution with the use of IV iron preparations in this population. The present review is intended to provide a brief overview of the potential adverse effects of the overzealous use of these agents.

Background Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) has been recognized as a distinct entity in recent years. To the best of our knowledge, all patients with PGNMID reported thus far were older than 20 years of age. We now report five cases of PGNMID in patients under 20 years of age. Methods The clinical database was searched for patients with native kidney biopsies from 9/2011 to 8/2017, and cases with a diagnosis of PGNMID were retrieved. Light microscopy specimens and immunofluorescence and electron microscopy images were revisited. Clinical data and kidney biopsy findings for patients under the age of 20 were recorded. Results Five (0.78%) of a total of 637 patients younger than 20 with native renal biopsies had a diagnosis of PGNMID, including three males and two females with an average age of 14 years old (range 10-19). All five patients presented with microscopic hematuria and proteinuria. Three patients were nephrotic and their C3 levels were low. All five cases showed a membranoproliferative pattern with abundant mesangial and subendothelial monoclonal IgG3 deposits (3 [kappa] and 2 [lambda] light chain, respectively). The patients were followed up to 56 months. Two patients had re-biopsies 28 and 18 months after initial diagnosis and both showed similar morphologic changes. Various treatments were attempted including prednisone, mycophenolate mofetil, tacrolimus, rituximab, and eculizmab, with mixed responses. Conclusions PGNMID does occur in children and young adults. Membranoproliferative glomerulonephritis pattern with monoclonal IgG3 deposits is a common feature. Despite various immunosuppressive treatments, the disease appears slowly progressive., Author(s): Guolan Xing [sup.1] , Robert Gillespie [sup.2] , Badreldin Bedri [sup.2] , Albert Quan [sup.3] , Pingchuan Zhang [sup.4] [sup.5] , Xin J. Zhou [sup.4] [sup.5] Author Affiliations: (Aff1) [...]

Oxidative stress plays an important role in the pathogenesis of anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBMGN). Superoxide dismutase (SOD) is the first line of defense against oxidative stress by converting superoxide to hydrogen peroxide ([H.sub.2][O.sub.2]). We investigated the effect of the SOD mimetic drug tempol on anti-GBM-GN in mice. 129/svJ mice were challenged with rabbit anti-mouse-GBM sera to induce GN and subsequently divided into tempol (200 mg x [kg.sup.-1] x [day.sup.-1], orally) and vehicle-treated groups. Routine histology, SOD and catalase activities, malondialdehyde (MDA), [H.sub.2][O..sub.2], and immunohistochemical staining for neutrophils, lymphocytes, macrophages, p65-NF-[kappa]B, and osteopontin were performed. Mice with anti-GBM-GN had significantly reduced renal SOD and catalase activities and increased H202 and MDA levels. Unexpectedly, tempol administration exacerbated anti-GBM-GN as evidenced by intensification of proteinuria, the presence of severe crescentic GN with leukocyte influx, and accelerated mortality in the treated group. Tempol treatment raised SOD activity and [H.sub.2][O.sub.2] level in urine, upregulated p65-NF-[kappa]B and osteopontin in the kidney, but had no effect on renal catalase activity. Thus tempol aggravates antiGBM-GN by increasing production of [H.sub.2][O.sub.2] which is a potent NF-[kappa]B activator and as such can intensify inflammation and renal injury. This supposition is supported by increases seen in p65-NF-[kappa]B, osteopontin, and leukocyte influx in the kidneys of the tempol-treated group. oxidative stress; catalase; hydrogen peroxide; crescentic glomerulonephritis; NF-[kappa]B doi: 10.1152/ajprenal.00583.2009.

Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody--induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that may be responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody--induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family, which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody--induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms, some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody--induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody--induced nephritis and lupus., Introduction Immune-mediated nephritis is an important pathogenic determinant in SLE and Goodpasture syndrome (anti--glomerular basement membrane [anti-GBM] disease). In spontaneous lupus nephritis, both Ab-mediated and Ab-independent mechanisms lead to renal [...]

Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan [...]

Mesangial cells are located within glomerular capillary loops and contribute to the physiological regulation of glomerular hemodynamics. The function of mesangial cells is controlled by a variety of ion channels in the plasma membrane, including nonselective cation channels, receptor-operated [Ca.sup.2+] channels, and recently identified store-operated [Ca.sup.2+] channels. Although the significance of these channels has been widely acknowledged, their molecular identities are still unknown. Recently, the members of the canonical transient receptor potential (TRPC) protein family have been demonstrated to behave as cation channels. The present study was performed to identify the isoforms of endogenous TRPC proteins in human mesangial cells (HMCs) and their interactions. Western blotting showed that TRPC 1, 3, 4, and 6 were expressed in cultured HMCs. Consistently, immunofluorescent confocal microscopy revealed specific stainings for TRPC1, 3, 4, and 6 with predominant intracellular localization. However, TRPC5 and 7 were not detectable at protein level by either Western blotting or immunofluorescent staining. The expression of TRPC1, 3, 4. and 6 was also observed in rat and human glomeruli using fluorescent immunohistochemistry. Furthermore, coimmunoprecipitation experiments and immunofluorescent double staining displayed that TRPC1 had physical interaction with TRPC4 and 6, while no interactions were detected among other isoforms of TRPCs. [Ca.sup.2+] fluorescent ratiometry measurement showed that store-operated [Ca.sup.2+] entry in HMCs was significantly reduced by knocking down TRPC1, but enhanced by overexpressing TRPC1 These results suggest that HMCs specifically express isoforms of TRPC1, 3, 4, and 6 proteins. These isoforms of TRPCs might selectively assemble to form functional complexes. store-operated [Ca.sup.2+] entry; [Ca.sup.2+] channel; [Ca.sup.2+] signaling; glomeruli

Ischemia-reperfusion induces G-CSF gene expression by renal medullary thick ascending limb cells in vivo and in vitro. Am J Physiol Renal Physiol 286: F1193-F1201, 2004. First published January 20, 2004; 10.1152/ajprenal.00379.2002.--Ischemic acute renal failure involves not only the kidney but also extrarenal organs such as the bone marrow that produces inflammatory cells. By ELISA and RNase protection assays, we now show that renal ischemia-reperfusion increases serum concentrations of granulocyte macrophage colony-stimulating factor (GCSF) protein and increases both G-CSF mRNA and protein in the ischemic kidney. In situ hybridization localized the increased G-CSF mRNA to tubule cells, including medullary thick ascending limb cells (mTAL), in the outer medulla. We also show that mTAL produce G-CSF protein and increase G-CSF mRNA after stimulation by reactive oxygen species in vitro. The production of G-CSF by the kidney after ischemia-reperfusion provides a means of communication from the injured kidney to the bone marrow. This supports the known inflammatory response to ischemia. acute renal failure; ischemia; granulocyte colony-stimulating factor; reactive oxygen species; medullary thick ascending limb tubules