Abstract 312: Jagged1 and Morphological Integrity of the Kidney

Abstract

Renal vascular development is dependent on the participation of renin precursor cells, which localize to areas of new vessel formation and differentiate into smooth muscle cells (SMCs), mesangial and juxtaglomerular (JG) cells. However, the mechanisms that enforce this particular fate of renin precursor cells remain unclear. During embryogenesis, renin cells express a significant number of angiogenic factors including the Notch signaling ligand Jagged1. We therefore hypothesized that Jagged1 is necessary for renin precursors to differentiate into the various mural cells of the renal arterioles and that Jagged1 plays a critical role in renal vascular development. To generate conditional Jagged1 deletion in cells of the renin lineage, we crossed Jagged1 fl/fl mice with Ren1d cre/+ mice. We investigated kidney weight, morphology, and vascular architecture as well as the identity of cells composing the kidney arterioles including renin cells and SMCs. We performed quantitative RT-PCR on kidney cortex mRNA for Jagged1 and Renin expression levels and immunohistochemistry for renin. The expression of Jagged1 mRNA in conditional knockout (cKO) animals was reduced at 2 weeks (68.3% reduction) and 4 weeks (66.5% reduction) compared to control mice. We found no significant differences between control and cKO animals in their kidney weights, renin mRNA expression, and renin staining. The number of renin-positive juxtaglomerular apparatuses (JGA) was 49.25 +/- 3.301 (n=4) and 38.00 +/- 4.830 (n=4) for control and cKO mice respectively under physiologic conditions. Staining for α-smooth muscle actin (α-SMA) demonstrated an overall normal vascular anatomy in cKO kidneys, however there were focal areas containing activated pericytes and injured mesangial cells expressing α-SMA indicating an active fibrotic process. Mason’s trichrome staining confirmed areas of glomerular and interstitial fibrosis in cKO kidneys. This work suggests that while Jagged1 is dispensable for renin expression, its loss in renin cell descendants affects perivascular-interstitial integrity and glomerular structure. The findings indicate an important role of Jagged1 in the maintenance of the morphologic integrity of the kidney.