Regulation of renin: new evidence from cultured cells and genetically modified mice.

Renin, as the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II, has been studied for more than 100 years. Transgenic and knockout mice for renin and other proteins involved in renin regulation and function have recently revealed new evidence that can improve our understanding of its biological relevance. Furthermore, transgenic mice have been the source of the novel cell line As4.1. This cell line has been effective in the analysis of renin secretion and regulation because of its similarity with renin-producing juxtaglomerular (JG) cells. Renin secretion and synthesis by the JG cells of the kidney is upregulated by cAMP and downregulated by intracellular calcium. The effect of cGMP, once elevated by nitric oxide, depends on the present level of cAMP in the cells, which can be stimulatory in the presence of and inhibitory in the absence of the other cyclic nucleotides. All known effectors of renin regulation affect one of these molecules. Adenosine and ATP, released by macula densa cells in response to high salt load in the distal tubule and stretch of the JG cell by renal perfusion pressure, increase calcium. Furthermore, noradrenaline, derived from sympathetic nerve endings, and prostaglandins, generated by macula densa cells under low-salt conditions, increase cAMP. In addition to its stimulatory effect on secretion, cAMP also effectively augments renin mRNA levels by acting at the transcriptional and posttranscriptional levels. Several DNA elements in the distal and proximal promoter regions as well as in intron I have been implicated in cAMP regulation and in tissue specificity of renin gene expression. A second intracellular renin isoform, coded by the same gene but applying a different promoter located in intron I, has recently been detected. Transgenic technology will help to clarify the function of this isoform as well as some of the other unresolved aspects of renin regulation and function and may become the motor of the second century in renin research.