Abstract 016: Cells Programmed for the Renin Phenotype Contribute to Vascular Pathology in Renin Deficient Mice

Abstract

Deletions of the renin-angiotensin system genes or pharmacological inhibition in early life result in a distinctive renal pathology: concentric and disorganized intra-renal arteriolar thickening. The origin and distribution of the cells contributing to the arterial disease are not known. Because the arteriolar thickening disappears with ablation of renin cells, we hypothesized that renin cell precursors contribute to the arterial pathology. To reveal the origin and distribution of the cells responsible for the arterial thickening we generated several mouse lines for fate tracing and also stained for cell identity specific proteins. Kidneys from Ren1c-/- (n=6) and Ren1c+/- (n=6) mice were immunostained for renin, αSMA and PECAM1. Arterial wall thickness was measured using a light microscope and the Leica MM AF ® version1.5 software. Renin cells (unable to produce renin because of the knock out) were identified using Ren1c-/-; Ren1c-YFP mice, where the yellow fluorescent protein is expressed by the Ren1c-YFP transgene designed to label all cells with an active renin promoter. In addition, we tracked the expression and distribution of aldo-keto reductase 1b7, AKR1b7, which mark cells programmed for the renin phenotype even when renin is absent. As expected, Ren1c-/- kidneys showed no renin and thicker intra-renal arteries (Arterioles: Ren1c+/- , 8.26 ± 2.5 μm vs. Ren1c-/- , 14.3 ± 3.8 μm, P<0.0001 , larger arteries: Ren1c+/- , 29.2 ± 11.1 μm vs. Ren1c-/- , 42.1 ± 11.1 μm, P<0.0001 ) AKR1b7+ and YFP+ cells were retained and observed throughout the renal arterioles. To investigate the fate and distribution of cells from the renin lineage, we used Ren1c-Cre and R26R.LacZ or mT/mG reporter mice (6 knock out and 6 control mice per strain). Cells from the renin lineage surrounded arterioles and persisted within larger arterial walls whereas PECAM1+ endothelial cells did not contribute to the arterial wall thickening. In control mice, renin cells were confined to the juxtaglomerular area. We conclude that precursor cells programmed for the renin phenotype maintain their molecular program and together with vascular smooth muscle cells contribute to nephro-vascular disease.