Unraveling the role of podocyte turnover in glomerular aging and injury

09.01.2014

Wanner N, Hartleben B, Herbach N, Goedel M, Stickel N, Zeiser R, Walz G, Moeller MJ, Grahammer F, Huber TB.

J Am Soc Nephrol. 2014;25(4):707-16

J Am Soc Nephrol.         online article

Podocyte loss is a major determinant of progressive CKD. Although recent studies showed that a subset of parietal epithelial cells can serve as podocyte progenitors, the role of podocyte turnover and regeneration in repair, aging, and nephron loss remains unclear. Here, we combined genetic fate mapping with highly efficient podocyte isolation protocols to precisely quantify podocyte turnover and regeneration. We demonstrate that parietal epithelial cells can give rise to fully differentiated visceral epithelial cells indistinguishable from resident podocytes and that limited podocyte renewal occurs in a diphtheria toxin model of acute podocyte ablation. In contrast, the compensatory programs initiated in response to nephron loss evoke glomerular hypertrophy, but not de novo podocyte generation. In addition, no turnover of podocytes could be detected in aging mice under physiologic conditions. In the absence of podocyte replacement, characteristic features of aging mouse kidneys included progressive accumulation of oxidized proteins, deposits of protein aggregates, loss of podocytes, and glomerulosclerosis. In summary, quantitative investigation of podocyte regeneration in vivo provides novel insights into the mechanism and capacity of podocyte turnover and regeneration in mice. Our data reveal that podocyte generation is mainly confined to glomerular development and may occur after acute glomerular injury, but it fails to regenerate podocytes in aging kidneys or in response to nephron loss.

Chronic loss of kidney function is of significant public health importance not only because of high prevalence but also because it is a major independent risk factor for cardiovascular morbidity and mortality.1 Aged kidneys display an increased susceptibility for progressive diseases, suggesting that overlapping molecular programs contribute to organ aging and disease progression.2 Recent data indicate that a decrease in the number of glomerular podocytes is an important predictor for kidney aging, and podocytes are considered the weak link in the progression of CKD.3 Animal models have shown that podocyte depletion of up to 20% can be tolerated before a scarring response takes place,4 but residual podocytes are unable to undergo cell division.5–7 Although it is widely believed that glomeruli have only a limited capacity to resolve lesions, cases of potential podocyte regeneration and disease reversal have been described.8–10 These recent observations have instigated hope of finding ways to stimulate kidney regeneration. So far, two potential podocyte progenitor niches, bone marrow cells and parietal epithelial cells, have been characterized.11–14 Bone marrow transplantation has an ameliorating effect in several animal models of glomerular disease,15–18 but the underlying mechanisms remain poorly understood. In humans, Y-chromosome–positive podocytes have been detected in kidneys transplanted from females to males.12 Located directly adjacent to podocytes, parietal epithelial cells express the stem cell markers CD24 and CD133 in human tissue and are capable of self-renewal, as well as differentiation into several cell types, including podocytes.11,14,19

In this study, a novel flow cytometry–based quantitative method was devised to assess the regenerative capacity of podocytes during diphtheria toxin (DT)–mediated acute podocyte loss, models of chronic nephron loss, and kidney aging.