A Slit in Podocyte Death

Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, de Madrid and IRSIN, Madrid, Spain.
Current Medicinal Chemistry (Impact Factor: 3.85). 02/2008; 15(16):1645-54. DOI: 10.2174/092986708784911542
Source: PubMed


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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    • "Podocytes are specialized epithelial cells that contribute critically to the kidney’s “filtration apparatus”. Podocyte dysfunction and/or damage has been associated with both acute and chronic glomerular diseases including focal segmental glomerulosclerosis, diabetic nephropathy and HIV nephropathy (1, 2, 3, 4–6). Podocyte depletion leads to glomerulosclerosis in murine models and recent studies suggest that short-lived localized insults can trigger a cascade of secondary damage that causes more global injury (7–9). "
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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; 83(6). DOI:10.1038/ki.2013.6 · 8.56 Impact Factor
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    Antioxidants & Redox Signaling 07/2009; 11(12):3071-109. DOI:10.1089/ARS.2009.2484 · 7.41 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(1):13. DOI:10.1186/1479-5876-9-13 · 3.93 Impact Factor
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