Abstract 39: The Macula Densa PGE2 Activates Adult Renal CD44+ Mesenchymal Stromal Cell (MSC) Migration and Differentiation to Renin Producing cells via EP4 Receptor and Wnt Canonical Signaling

Background: We have previously shown that CD44+ MSCs exist in the adult kidney and that under chronic sodium deprivation these cells migrate to the juxtaglomerular (JG) area and differentiate to new renin expressing cells. The mechanisms mediating these biological processes remain elusive. Renin expression and release by JG cells is initiated at the Macula densa (MD) primarily by the release of PGE2. Interestingly, renal MSC expresses the PGE2 receptor EP4. Here, we hypothesized that MD-derived PGE2 acting via the EP4 is responsible for the migration of renal MSCs and their differentiation to renin expressing cells. Methods: MSCs were isolated by FACS from the kidney of C57BL/6 adult mice and co-cultured in a transwell system with the MD cell line MMDD1 at normal or low NaCl medium. For the in vivo study, wild type and EP4 knockout mice were fed a low salt diet and given furosemide to induce JG hyperplasia. Renin, CD44 and B-catenin stabilization were detected by immunochemistry staining and Western blot analysis. Results: Low salt stimulation of MMDD1 cells significantly increased MSC migration in transwell assays (P Conclusion: The MD/ PGE2/ EP4 axis plays a key role in the activation of MSCs and their differentiation to renin producing cells. This process could potentially be an important physiologic mechanism of maintaining blood pressure under conditions of sodium deprivation.