Abstract P091: Role Of Gata3 In Renin Cell Identity

Abstract

Renin cells act as precursors for other cell types in the kidney vasculature and show high plasticity in postnatal life in response to challenges to homeostasis. Our scRNA-seq studies revealed that the dual-zinc finger transcription factor (TF) Gata3, important for cell lineage commitment and differentiation in several tissues, is expressed in mouse renin cells under normal conditions and homeostatic threat. In addition, we found an enhancer associated with Gata3 in renin cells leading us to hypothesize that GATA3 is important for renin cell identity. We studied 60 and 76 day-old mice carrying a conditional deletion of Gata3 in renin cells: Gata3fl/fl;Ren1dCre/+ (Gata3 cKO), and control Gata3fl/fl;Ren1+/+ counterparts. Gata3 cKO mice exhibited increased BUN (43±4.6mg/dl) vs. control mice (BUN: 21±2mg/dl), suggestive of hypovolemia and/or compromised renal function. By immunostaining, renin expressing cells appeared very thin compared to the normal plump shape in control mice. Renin signal was abnormally localized to the Bowman’s capsule in some glomeruli, and there was an atypical strong Acta2 signal in the mesangium and Bowman’s capsule in Gata3 cKO mice. Distal tubules showed dilated morphology without visible intraluminal casts whereas proximal tubules appeared normal. Gata3 cKO recruited mice exhibited marked reductions in Ren1+ cells compared to controls by an 87% reduction of Ren1 mRNA levels by RT-qPCR (1.68 ± 0.11 vs 12.98 ± 0.98, p=0.0006). H&E, PAS, and Mason’s Trichrome reactions demonstrated increased glomerular fusion, absent cubical epithelial cells in Bowman’s capsule, and intraglomerular aneurysms. In summary, we found abnormal expression and localization of Ren1 and Acta2 and abnormal morphology of kidneys in Gata3 cKO mice. Our results suggest a role of Gata3 in the identity of cells of the renin lineage. Future studies will investigate the role of Gata3 during development and in older animals.