SALT RESTRICTION LEADS TO ACTIVATION OF ADULT RENAL MSC-LIKE CELLS VIA PGE2 AND EP4 RECEPTOR

Despite the importance of juxtaglomerular (JG) cell recruitment in the pathophysiology of cardiovascular diseases, the mechanisms that underlie renin production under conditions of chronic stimulation remain elusive. We have previously shown that CD44+ mesenchymal-like cells (CD44+ cells) exist in the adult kidney. Under chronic sodium deprivation these cells are recruited to the JG area and differentiate to new renin-expressing cells. Given the proximity of macula densa (MD) to the JG area and the importance of MD released prostanoids in renin synthesis and release, we hypothesized that chronic sodium deprivation induces MD release of prostanoids; stimulating renal CD44+ cell activation and differentiation. CD44+ cells were isolated from adult kidneys and co-cultured with the MD cell line, MMDD1, in normal or low sodium medium. Low sodium stimulated PGE2 production by MMDD1 and induced migration of CD44+ cells. These effects were inhibited by addition of a Cox-2 inhibitor (NS398) or an EP4 receptor antagonist (AH23848) to MMDD1 or CD44+ cells respectively. Addition of PGE2 to CD44+ cells increased cell migration and induced renin expression. In vivo activation of renal CD44+ cells during JG recruitment was attenuated in wild type mice subjected to salt restriction in the presence of Cox-2 inhibitor Rofecoxib. Similar results were observed in EP4 receptor knockout mice subjected to salt restriction. These results show that the PGE2/ EP4 pathway plays a key role in the activation of renal CD44+ MSC-like cells during conditions of JG recruitment; highlighting the importance of this pathway as a key regulatory mechanism of JG recruitment.