Podocyte injury can be catching.

Podocyte loss is a central mediator of glomerular sclerosis. Because podocytes are terminally differentiated cells that lack the potential to proliferate, they are particularly vulnerable to attrition in response to critical levels of cell stress, leading to detachment, necrosis, or apoptosis. Just how much podocyte loss is necessary to generate an initial sclerotic lesion and whether injury can propagate to other podocytes remain controversial. Podocyte depletion and podocyturia have been documented in many chronic renal diseases, including FSGS, IgA nephropathy, and diabetic nephropathy, among others.1–3 The concept of podocyte depletion as a cause of glomerulosclerosis originates with the seminal ultrastructural studies by Nagata and Kriz4 in an ablation model of FSGS produced by uninephrectomy in the young rat. As glomeruli hypertrophy in response to loss of functioning nephrons, the terminally differentiated podocytes must stretch to provide cover for the enlarging glomerular tuft. The podocyte’s capacity to hypertrophy is limited, and sites of tuft denudation caused by individual podocyte failure and detachment become covered by parietal epithelial cells, forming a nidus for the development of segmental scars. This groundbreaking observation led Nagata and Kriz4 to formulate the thesis of podocytopenia in the development of segmental sclerosis. More recently, investigators exploited genetic engineering in the mouse to test whether podocyte depletion per se is sufficient to cause FSGS. A number of ingenious toxin models can deliver a lethal dose of toxin specifically and exclusively to the podocyte, sparing all other renal cell types.5–7 By producing a transgenic animal that expresses a toxin receptor under the control of a podocyte-specific promoter, these models allow the severity of podocyte injury over time to be correlated directly with the onset, dosage, and duration of toxin exposure. In a transgenic rat model, human diphtheria toxin receptor was expressed under the podocin promoter.7 Because the rat homologue of the diphtheria toxin receptor does not recognize diphtheria toxin, only podocytes bearing the human receptor are able to internalize toxin. After injection of diphtheria toxin, which causes cell death by inhibition of protein synthesis, the extent of podocyte depletion correlates with the size of the segmental lesions and the severity of proteinuria. A threshold of 40% podocyte depletion produces the full-blown picture of FSGS with nephrotic proteinuria and reduction in renal function, whereas 60% loss leads to global sclerosis and severe renal failure. In the NEP25 model, Matsusaka et al.6 produced a transgenic mouse that expresses human (h) CD25 driven by the nephrin promoter. FSGS develops within 2 to 4 weeks after injection of recombinant immunotoxin, a fusion protein composed of the variable domain of anti-hCD25 antibody and Pseudomonas exotoxin A as toxin moiety, which similarly kills cells by inhibition of ADP ribosylation of polypeptide chain elongation factor 2 that is required for protein synthesis. Whereas areas of denuded glomerular basement membrane (GBM) become covered by parietal epithelial cells8,9 that migrate onto the tuft,5 only coverage by differentiated podocytes equipped with foot processes and slit diaphragms can reconstitute a normal glomerular filtration barrier.5 In this issue of JASN, Matsusaka et al.10 report a fascinating twist on the NEP25 toxin model devised to address the issue of local propagation of cell injury. By engineering a chimeric model in which only a subset of podocytes bear the hCD25 toxin receptor and the remainder are permanently genetically labeled with a durable tag, human placental alkaline phosphatase (PLAP), they have been able to map cell fate precisely after toxin exposure. Because the two mutually exclusive podocyte populations are variably admixed in individual glomeruli, this model has the advantage of producing a spectrum of chimeras in which from 2 to 99% of podocytes carry the toxin receptor, allowing a broad range of toxin effect to be monitored. In addition, because the PLAP tag is retained after injury, the receptor-negative podocytes can be identified even if they become dedifferentiated. The provocative findings from this study shed new light into the ability of podocyte injury to propagate to neighboring cells that escape the initial insult.10 Toxin exposure produced rapid cell death in hCD25-positive podocytes with massive proteinuria at 4 days, followed by a wave of secondary injury to podocytes lacking the toxin receptor. In this later phase, which was evident 6 weeks after the initial assault, PLAP-positive podocytes display foot process effacement and downregulation of podocyte maturity markers, nephrin, podocin, and vascular endothelial growth factor together with upregulation of injury marker desmin. Importantly, the percentage of hCD25negative podocytes with this dysregulated phenotype correlated with the percentage of hCD25-positive podocytes at baseline, indicating that the more cells that are damaged directly by toxin, the more toxin-resistant cells will be injured later in the secondary wave. The secondary injury often occurred at sites adjacent to sclerotic lesions, suggesting a phenomenon of localized cell-to-cell spread of injury that is driven by initial podocyte injury and loss, rather than a generalized adaptive response. By contrast, chimeras with few ( 25%) toxin-susPublished online ahead of print. Publication date available at www.jasn.org.