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EDITORIAL FOCUS

Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gs in juxtaglomerular cells

¹National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and ²University of Virginia, Charlottesville, Virginia

Submitted 3 May 2006 ; accepted in final form 21 June 2006

By crossing mice with expression of Cre recombinase under control of the endogenous renin promoter (Sequeira Lopez ML, Pentz ES, Nomasa T, Smithies O, Gomez RA. Dev Cell 6: 719–728, 2004) with mice in which exon 1 of the Gnas gene was flanked by loxP sites (Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT, Nackers LM, Lorenzo J, Shen L, Weinstein LS. Proc Natl Acad Sci USA), we generated animals with preferential and nearly complete excision of Gs in juxtaglomerular granular (JG) cells. Compared with wild-type animals, mice with conditional Gs deficiency had markedly reduced basal levels of renin expression and very low plasma renin concentrations. Furthermore, the acute release responses to furosemide, hydralazine, and isoproterenol were virtually abolished. Consistent with a state of primary renin depletion, Gs-deficient mice had reduced arterial blood pressure, reduced levels of aldosterone, and a low glomerular filtration rate. Renin content and renin secretion of JG cells in primary culture were drastically reduced, and the stimulatory response to the addition of PGE₂ or isoproterenol was eliminated. Unexpectedly, Gs recombination was also observed in the renal medulla, and this was associated with a vasopressin-resistant concentrating defect. Our study shows that Cre recombinase under control of the renin promoter can be used for the excision of floxed targets from JG cells. We conclude that Gs-mediated signal transduction is essential and nonredundant in the control of renin synthesis and release.

juxtaglomerular granular cell culture; furosemide; hydralazine; aldosterone; cyclooxygenase 2; urine concentration

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