RENIN-1 IS ESSENTIAL FOR NORMAL RENAL JUXTAGLOMERULAR CELL GRANULATION AND MACULA DENSA MORPHOLOGY

The secretion of renin from granules stored in renal juxtaglomerular c ells plays a key role in blood pressure homeostasis. The synthesis and release of renin and the extent of granulation is regulated by severa l mechanisms including signaling from the macula densa, neuronal input , and blood pressure. Through the use of a gene-targeting vector conta ining homology arms generated using the polymerase chain reaction, we have inactivated the Ren-1(d) gene, one of two mouse genes encoding re nin, and report that lack of renin-1(d) results in altered morphology of the macula densa of the kidney distal tubule and complete absence o f juxtaglomerular cell granulation. Furthermore, Ren-1(d-/-) mice exhi bit sexually dimorphic hypotension. The altered growth morphology of t he macula densa in Ren-1(d)-null mice should provide a tool for the in vestigation of the JG cell-macula densa signaling. Furthermore, the cu rrent data indicate that expression of the Ren-1(d) gene is a prerequi site for the formation of storage granules, even though the related pr otein renin-2 is present in these mice, suggesting that renin-1(d) and renin-2 are secreted by distinct pathways in vivo.