Renin-Angiotensin-Aldosterone System Inhibition Increases Podocyte Derivation from Cells of Renin Lineage

Abstract

Because adult podocytes cannot proliferate and are therefore unable to self-renew, replacement of these cells depends on stem/progenitor cells. Although podocyte number is higher after renin-angiotensin-aldosterone system (RAAS) inhibition in glomerular diseases, the events explaining this increase are unclear. Cells of renin lineage (CoRL) have marked plasticity, including the ability to acquire a podocyte phenotype. To test the hypothesis that RAAS inhibition partially replenishes adult podocytes by increasing CoRL number, migration, and/or transdifferentiation, we administered tamoxifen to Ren1cCreERxRs-tdTomato-R CoRL reporter mice to induce permanent labeling of CoRL with red fluorescent protein variant tdTomato. We then induced experimental FSGS, typified by abrupt podocyte depletion, with a cytopathic antipodocyte antibody. RAAS inhibition by enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin-receptor blocker) in FSGS mice stimulated the proliferation of CoRL, increasing the reservoir of these cells in the juxtaglomerular compartment (JGC). Compared with water or hydralazine, RAAS inhibition significantly increased the migration of CoRL from the JGC to the intraglomerular compartment (IGC), with more glomeruli containing RFPCoRL and, within these glomeruli, more RFPCoRL. Moreover, RAAS inhibition in FSGS mice increased RFPCoRL transdifferentiation in the IGC to phenotypes, consistent with those of podocytes (coexpression of synaptopodin and Wilms tumor protein), parietal epithelial cells (PAX 8), and mesangial cells (α8 integrin). These results show that in the context of podocyte depletion in FSGS, RAAS inhibition augments CoRL proliferation and plasticity toward three different glomerular cell lineages.

Persistent and inducible neogenesis repopulates progenitor renin lineage cells in the kidney

“…This maneuver increases the number of renin-producing cells in AA mainly by reversible metaplastic transformation and limited proliferation within the RLC population. 1,17,20 Although recruitment of RLCs capable of reexpressing renin is the predominant mechanism, our current data indicate neogenesis to be an additional process.…”

“…10 Other researchers have reported that RLCs might give rise to glomerular epithelial cells such as parietal epithelial cells and podocytes, following the induction of experimental FSGS in mice. 12,20 These findings were intriguing because unlike mesangial cells or parietal epithelial cells, podocytes do not belong to the RLC population in the healthy adult mouse kidney (Figure 1). All these findings led us to question whether the RLC pool in the kidney is continuously maintained.…”

“…It is plausible to assume that after injury, further glomerular epithelial cells types could be replenished through a similar process because RLCs appear to have the potential to differentiate into parietal epithelial cells and podocytes after FSGS. 12,20 …”

“…The recently described RLC proliferation was observed only after RASi (with or without additional renal injury) and was absent in the adult kidney under basal conditions. 20 It should also be noted that reversible metaplastic transformation is not related to the filling up of the RLC niche because it represents a phenotype switch within the RLC pool.…”

New Anti-Nephrin Antibody Mediated Podocyte Injury Model Using a C57BL/6 Mouse Strain

“…However, the Adriamycin (doxorubicin) nephritis model of FSGS cannot be induced in the C57BL/6 strain ( Table 1) [8], which is doxorubicin-resistant due to differences in Pheromoneregulated protein 7 [4]. Another FSGS model can be induced in the C57BL/6 strain by anti-glomerular antibody [9][10][11][12][13][14][15]. The targets of this antibody have not been elucidated because it is unknown whether this antibody recognizes the podocyte or other glomerular component(s).…”