Regulated tissue- and cell-specific expression of the human renin gene in transgenic mice

Abstract

Transgenic mice containing the human renin gene were constructed with the aim of examining the tissue-and cell-specific expression of human renin. The human renin transgene used consisted of a genomic sequence extending approximately 900 bp upstream and 400 bp downstream of the coding region and included all exon and intron sequences. Two assays were developed to differentiate human renin transcripts from endogenous mouse renin transcripts at the whole-tissue level. High level human renin expression was evident in the kidney, adrenal gland, ovary, testis, lung, and adipose tissue of all four transgenic lines examined. Human renin mRNA could also be detected at lower levels in the submandibular gland and heart of two different individual lines. No expression was evident in the liver or brain of any line tested. In situ hybridization revealed the human renin mRNA to be localized and exquisitely restricted to renal juxtaglomerular cells. Treatment of transgenic mice with captopril resulted in an increase in the accumulation of renal renin mRNAs derived from both the mouse and human renin genes. Plasma renin activity assays using synthetic human renin substrate clearly demonstrated the elaboration of active human renin into the systemic circulation of transgenic mice. These data strongly suggest that the human renin transgene exhibits both tissue- and cell-specific expression in transgenic mice. Its expression is entrained to the same regulatory signals as the endogenous renin gene in kidney, and active human renin is released into the plasma of the transgenic mice. Therefore, important cis-acting regulatory sequences controlling tissue-specific human renin expression lie within a genomic segment encompassing all exon and intron sequences and including sequences extending 900 bp upstream and 400 bp downstream of the gene. (Circulation Research.