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    • To establish whether replacement of lost podocytes by

    2018-10-24

    To establish whether replacement of lost podocytes by RPCs could influence CKD outcome, we traced podocyte regeneration to compare mice that underwent proteinuria remission with those that developed persistent proteinuria and CKD using two different lineage-tracing strategies. By tracking podocytes or RPCs, we consistently observed that proteinuria remission was associated with regeneration by RPCs of 5%–10% of total kidney podocytes. Since nephrotic syndrome in these mice caused a 15%–20% podocyte loss, this corresponds to regeneration of approximately one-third of lost podocytes. By contrast, in mice that developed persistent proteinuria and CKD, podocyte regeneration was irrelevant. The Pax2.rtTA;TetO.Cre;mT/mG model also allowed us to establish that RPCs are the source of podocyte regeneration after injury. Indeed, in mice that underwent proteinuria remission after injury, ∼30% of lost podocytes were replaced by new podocytes generated by PAX2+ cells. By contrast, the percentage of PAX2+cell-derived podocytes was irrelevant in mice with persistent proteinuria. The virtually identical results observed once the same experimental strategy was established in Pax2.rtTA;TetO.Cre;mT/mG as well as in NPHS2.iCreER;mT/mG mice demonstrates that RPCs are the source of podocyte regeneration. From pathology studies in transplanted patients, we know that an increase of 20% of podocyte mass can efficiently compensate a reduction of 50% of zolmitriptan surface (Song et al., 2014). Thus, the amount of podocyte replacement that can be provided by RPCs represents a substantial possibility of recovery that can critically determine the outcome of a glomerular disorder. Consistently, we know that the glomerulus can recover from up to a 20% reduction in podocyte density occurring over a short period of time (Wiggins, 2007). By contrast, as >30% podocyte depletion occurs, glomerular stress and further podocyte depletion supervene, triggering glomerulosclerosis and ESRD (Fukuda et al., 2012). Taken together, these results demonstrate that when RPCs acquire phenotypic and functional features of fully differentiated podocytes, proteinuria remission occurs, while when progenitor differentiation is not effective, proteinuria persists and glomerular scars emerge. The pivotal role played by PECs in the pathogenesis of intraglomerular scars in FSGS was recently suggested by several studies (Shankland et al., 2014; Smeets et al., 2009; Lasagni and Romagnani, 2010). The results of this study demonstrate that glomerular scars are caused by an inefficient differentiation into mature podocytes of those PECs that represent RPCs. Based on this observation, we reasoned that RPCs may represent a therapeutic target and that enhancing RPC differentiation into podocytes could reduce formation of glomerular scars and promote podocyte regeneration and proteinuria remission. To evaluate if enhancement of RPC differentiation into podocytes may represent an attractive therapeutic strategy to promote remission of glomerular disorders, we screened a library of small molecules for their potential to promote RPC differentiation into podocytes. Among the molecules analyzed, we identified the GSK3 inhibitor BIO as a strong promoter of hRPC differentiation toward podocytes in vitro and in vivo. We also demonstrated that BIO acts by increasing RA binding to its specific RARE elements and by enhancing RPC sensitivity to the differentiation effect of endogenously produced RA. Indeed, RA is a podocyte differentiation factor that is released within the Bowman’s space following glomerular injury (Peired et al., 2013). Interestingly, it was previously shown that albuminuria sequesters RA within the Bowman’s space and administration of RA reduces proteinuria in mice with Adriamycin nephropathy (Peired et al., 2013). However, doses of RA that are toxic in humans are needed to rescue the effects of albuminuria (Tallman et al., 2000). Enhancement of RPC differentiation into podocytes by using BIO avoided toxicity and significantly improved the disease outcome. This observation demonstrates that the course of CKD can be shifted from progression to remission by acting on the RPC response to injury.