Genetic Disruption of Secreted Renin with Preservation of Intracellular Renin Causes Cardiovascular Dysregulation and Interfered Metabolism

Abstract

Secreted renin (sRen) is translated into preprorenin, whereas intracellular renin (icRen) initiates transcription from an alternative promoter, uses a new 1st exon (exon‐1b) and translates from an alternative highly conserved ATG. Since icRen lacks the signal peptide it remains intracellular. We performed gene targeting to ablate sRen while preserving icRen. +/‐ mice carrying the null allele were intercrossed but only two ‐/‐ mice survived (+/+ 34; +/‐ 69; ‐/‐ 2). Daily saline injections of newborns allowed us to rescue additional ‐/‐ survivors that exhibited renal atrophy, lower blood pressure and heart rate, a blunted baroreflex, less brown adipose, and lower body weight. Timed breedings between +/‐ mice were performed to obtain ‐/‐ tissues at 18.5gd. +/+, +/‐ and ‐/‐ fetuses were obtained in expected numbers (7:20:9). Expression of sRen and icRen mRNAs in brain and kidney were detected in +/+ and +/‐ fetuses. ‐/‐ fetuses had no sRen mRNA in kidney and brain, but retained expression of icRen mRNA. We conclude: 1) deleting sRen does not affect icRen mRNA, 2) preservation of icRen is insufficient to rescue lethality caused by loss of sRen, and 3) adult sRen ‐/‐ exhibit cardiovascular and metabolic dysregulation. We are breeding the floxed allele to Nestin/GFAP‐CRE mice to generate brain‐specific KOs of sRen while preserving icREN to examine the physiological relevance of intracellular renin in the brain.