Angiotensin Type 1 Receptor Blocker Restores Podocyte Potential to Promote Glomerular Endothelial Cell Growth

Abstract

Both podocytes and glomerular endothelial cells (GEN) are postulated to play important roles in the progression and potential regression of glomerulosclerosis. Inhibition of angiotensin is crucial in treatment of chronic kidney disease, presumably via effects on BP and extracellular matrix. This study aimed to investigate how angiotensin inhibition altered the interactions between podocytes and GEN. The effects of supernatants from primary cultured mouse podocytes, before or after sublethal injury by puromycin aminonucleoside, in the presence or absence of angiotensin type 1 receptor blocker (ARB), on GEN sprouting and growth were assessed. Supernatant from normal podocytes significantly increased GEN sprouting, whereas puromycin aminonucleoside-injured podocyte supernatant decreased these GEN responses. These effects were linked to decreased vascular endothelial growth factor A (VEGF-A) and angiopoietin-1 (Ang-1) protein from injured podocytes. This downregulation of VEGF-A and Ang-1 protein was reversed when injured podocytes were treated with ARB. Inhibition of VEGF-A or Ang-1 prevented this restored response by ARB. Activation of intracellular kinases (p38, extracellular signal-regulated kinase, and AKT) was suppressed in GEN that were treated with medium from injured podocytes but restored by medium from ARB-treated injured podocytes. Therefore, injured podocytes are ineffective in promoting GEN sprouting, and this effect is reversed by ARB treatment of the injured podocyte. These data support the idea that ARB effects on podocytes may mediate capillary remodeling in vivo.