Abstract 090: Cells Of The Renin Lineage Promote Kidney Regeneration Post - Release Of Ureteral Obstruction In Neonatal Mice.

Abstract

Renin, the rate-limiting enzyme of the renin-angiotensin system, is increased in the kidneys subjected to ureteral obstruction. We elucidated the changes and contribution of renin-producing cells (RPCs) and the cells of renin lineage (CoRL) during kidney damage and regeneration using a partial unilateral ureteral obstruction (pUUO) model in neonatal mice. Renin cells were ablated by cell-specific expression of diphtheria toxin A chain (DTA) and labeled with GFP. We compared the cell fate changes between kidneys from the wild-type (WT) and the DTA-expressing animals, using the pUUO model. The kidneys of 3W old DTA-positive Ren1 dDTA/+ ;R26R DTA/+ and Ren1 dCre/+ ;R26R DTA/+ genotypes were grossly normal. We observed no significant differences in the Myh11-positive renal vascular area between the WT and the DTA-positive mice (WT-3W: 1.72±0.10 % (n=6), Ren1 dDTA/+ ;R26R DTA/+ -3W: 1.94 ±0.123 % (n=7), Ren1 dCre/+ ;R26R DTA/+ -3W: 2.017±0.16% (n=4)). In the kidneys of the WT group, RPCs and the CoRL significantly increased at 3W post-obstruction and the distribution was similar to the sham-operated kidneys at 2W post-relief of obstruction (Renin-positive area-WT: Sham-3W: 0.57±0.02% (n=6), Obstructed-3W: 1.59±0.44% (n=4), Post-release-2W: 0.71±0.12% (n=3)). There was a significant decrease in RPCs in the DTA animals, and the reduction of RPCs and CoRL was markedly higher in Ren1 dCre/+ ;R26R DTA/+ mice in comparison to Ren1 dDTA/+ ;R26R DTA/+ group. Also, the DTA-positive animals did not respond to pUUO with a significant increase in renin as in the WT (Renin-positive area: Ren1 dDTA/+ ;R26R DTA/+ Sham-3W: 0.13±0.048% (n=5), Obstructed-3W: 0.23±0.10% (n=5), Post-release-2W: 0.14±0.04% (n=9) Ren1 dCre/+ ;R26R DTA/+ Sham: 0.010±0.004% (n=4), Obstructed: 0.07±0.004% (n=4), Post-release: 0.03±0.004% (n=3)). The renal fibrotic area and Tgfb1 mRNA levels post-obstruction and relief of obstruction were significantly high in Ren1 dCre/+ ;R26R DTA/+ group in comparison to Ren1 dDTA/+ ;R26R DTA/+ genotype due to the depletion of CoRL. Thus, our current study reveals that CoRL undergoes cell fate changes in response to obstruction and the release of obstruction, and these changes play a critical role in promoting kidney regeneration post-relief of obstruction.