Abstract P392: Prdm6 Is An Embryonic Regulator Of Renin-producing Cells And Its Loss Of Function Causes Hypertension In Humans

Le résumé fourni par la source

Essential hypertension is an inherited disease but its genetic causes are vastly not known. Genome-wide association studies (GWAS) have identified 5q23 as one of the strongest loci for hypertension in numerous populations with diverse ethnic backgrounds. Using massively parallel reporter and gene editing assays, we identified PRDM6 as the causal gene for hypertension at the 5q23 locus. Accordingly, mice deficient in smooth muscle cell (SMC) PRDM6 (Prdm6 fl/+ SM22-Cre )developed hypertension on a high salt diet. Mechanistically, loss of PRDM6 impaired the differentiation of renin-producing cells into smooth muscle cells, Sox6-dependent upregulation of renin-producing cells, and led to elevated plasma renin levels. Consistent with these findings, SMC-specific Sox6 KO mice exhibited very few renin-producing cells and normalized renin levels when they were intercrossed with Prdm6 fl/+ SM22-Cre mice. The blood pressure of Prdm6 fl/+ SM22-Cre mice was normalized with the renin inhibitor aliskiren. Strikingly, transcriptome analysis of the aorta showed that PRDM6 regulates 46 genes that are at GWAS peak loci for hypertension. These findings identify PRDM6 as a master regulator for blood pressure and as an attractive target for the development of antihypertensive drugs.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.