A slit in podocyte death.
ABSTRACT Recent advances have identified the podocyte as a key target in glomerular injury. The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity for proteins in the kidney. Podocyte injury or loss leads to proteinuria. Apoptosis has been shown to contribute to renal cell loss, including loss of podocytes. The most striking feature of the podocyte is its ability to form intricate specialized cell junctions, the slit diaphragm. Slit diaphragm proteins play an important role in podocyte biology, protein permselectivity, cell signalling and disease. This review focuses on recent advances on the understanding of podocyte survival regulation, its relationship to slit diaphragm structure and function, and how this knowledge may affect our therapeutic approach to proteinuric kidney disease.
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ABSTRACT: Podocytes are specialized cells that contribute critically to the normal structure and function of the glomerular filtration barrier. Their depletion plays an important role in the pathogenesis of glomerulosclerosis. Here, we report generation of a genetic model of conditional podocyte ablation and regeneration in zebrafish using a bacterial nitroreductase strategy to convert a prodrug, metronidazole, into a cytotoxic metabolite. A transgenic zebrafish line was generated that expresses green fluorescence protein (GFP) and the nitroreductase fusion protein under the control of the podocin promoter Tg(podocin:nitroreductase-GFP). Treatment of these transgenic zebrafish with metronidazole results in podocyte apoptosis, a loss of nephrin and podocin expression, foot process effacement, and a leaky glomerular filtration barrier. Following metronidazole washout, proliferating cells were detected in the glomeruli of recovering transgenic fish with a restoration of nitroreductase-GFP fluorescence, nephrin and podocin expression, a reestablishment of normal foot process architecture, and glomerular barrier function. Thus, our studies show that zebrafish podocytes are capable of regenerating following depletion, and establish the Tg(podocin:NTR-GFP) fish as a new model to study podocyte injury and repair.Kidney International advance online publication, 6 March 2013; doi:10.1038/ki.2013.6.Kidney International 03/2013; · 8.52 Impact Factor
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ABSTRACT: Transforming growth factor-β1 (TGF-β1) and the macrophage inhibitory factor receptor CD74 link the metabolic disorder with tissue injury in diabetic nephropathy. Fabry disease is an X-linked lysosomal glycosphingolipid storage disorder resulting from a deficient activity of α-galactosidase A that leads to proteinuric renal injury. However, the link between the metabolic abnormality and renal injury is poorly characterized. Globotriaosylsphingosine (lyso-Gb3) was recently identified as a bioactive molecule accumulating in Fabry disease. We hypothesized that lyso-Gb3 could modulate the release of secondary mediators of injury in glomerular podocytes and that recently described nephroprotective actions of vitamin D receptor activation in diabetic nephropathy may apply to lyso-Gb3. Real time RT-PCR, ELISA and Western blot were used to study the biological activity of lyso-Gb3 in cultured human podocytes and potential modulation by vitamin D receptor activation. In human podocytes, lyso-Gb3 dose and time dependently increased the expression of TGF-β1, extracellular matrix proteins (fibronectin and type IV collagen) and CD74. TGF-β1 mediated lyso-Gb3 effects on extracellular matrix production. Vitamin D receptor activation with paricalcitol or calcitriol prevented the increase in TGF-β1, CD74 and extracellular matrix induced by lyso-Gb3. Lyso-Gb3 may have a role in glomerular injury in Fabry disease by promoting the release of secondary mediators of glomerular injury common to diabetic nephropathy. These effects are prevented by paricalcitol, raising the issue of vitamin D receptor activation as potential adjunctive therapy in Fabry nephropathy.Nephrology Dialysis Transplantation 06/2011; 26(6):1797-802. · 3.37 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed.Journal of Translational Medicine 01/2011; 9:13. · 3.46 Impact Factor