Abstract MP25: Defining The Role Of Renin Lineage Cells During Regeneration After Release Of Partial Ureteral Obstruction In Neonatal Mice.

Abstract

Our previous study on a partial unilateral ureteral obstruction (pUUO) model in neonatal mice showed that the release of obstruction halts the progression of kidney damage and leads to a remarkable repair of the kidney with improvement in renal blood flow. In the current study, we aim to understand the role of mural cells of the renin lineage during kidney damage and repair in the neonatal pUUO model. Our results show a marked increase in renin-positive areas in kidneys obstructed for 3W (Sham-3W: 0.70±0.10%, n=3; Obstructed-3W: 1.82±0.43%, n=3). However, relief of obstruction at 1W restored the renin-positive areas to sham levels (Post-release-2W: 0.70±0.09%; n=3). Lineage tracing using Ren1 d Cre;mTmG mice revealed a significant increase in GFP+ cells in the obstructed kidneys, with a decrease post-release. To understand further the dynamic changes in cells of renin lineage due to obstruction, we ablated the renin cells using DTA (Diphtheria toxin subunit A). We crossed the DTA fl/fl mice with Ren1 d -DTA het ;Ren1 d Cre;mTmG mice and performed pUUO in the resultant pups with DTA in the renin cells (DTA+). DTA+ animals showed thinning of the renal vasculature and a 90% reduction in renin-positive area compared to controls [Control: 0.70±0.10% (n=3); DTA+: 0.06±0.03% (n=3)]. In addition, there was no significant increase in the renin-positive area post-obstruction [Sham-3W: 0.06±0.04% (n=3); Obstructed-3W: 0.12±0.05% (n=4); Post-release-2W: 0.08±0.03% (n=4)]. These results indicate that ablation of renin cells abolished the obstruction-mediated surge in the renin expression. However, measurement of interstitial collagen positive area indicated that despite the absence of renin cells, the fibrotic damage due to obstruction recovered remarkably post-release [Collagen positive area: Sham-3W: 3.38±0.67% (n=3) Obstructed-3W: 62.98±31.50% (n=3); Post-release-2W: 10.93±5.46% (n=4)]. Similarly, vascular damage induced by persistent obstruction and recovery following the relief of obstruction was similar between the DTA+ and non-DTA animals. Our results imply that though the renin and renin lineage cells increase in obstructed kidneys, ablation of renin cells does not affect the regeneration capacity of kidneys following the relief of obstruction.