title: 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 RFP+CoRL and, within these glomeruli, more RFP+CoRL. Moreover, RAAS inhibition in FSGS mice increased RFP+CoRL 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.
authors.affiliation: Division of Nephrology and.
authors.forename: Julia
authors.initials: J
authors.lastname: Lichtnekert
authors.affiliation: Division of Nephrology and.
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Kaverina
authors.affiliation: Division of Nephrology and.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Eng
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Gross
authors.affiliation: Department of Applied Mathematics, University of Washington, Seattle, Washington; and.
authors.forename: J Nathan
authors.initials: JN
authors.lastname: Kutz
authors.affiliation: Division of Nephrology and.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pippin
authors.affiliation: Division of Nephrology and stuartjs@u.washington.edu.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects; D012083:Renin / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D012083:Renin; D019808:Losartan
keywords: ACE inhibitors; focal segmental glomerulosclerosis; podocyte