Intracellular cAMP,theproductionof whichis catalyzedby thea-subunit of thestimulatoryGprotein (Gsa), controls renin synthesis and release by juxtaglomerular (JG) cells of the kidney, but may also have relevance for the physiologic integrity of the kidney. To investigate this possibility, we generated mice with inducible knockout ofGsa in JG cells and monitored them for 6 months after induction at 6 weeks of age. The knockoutmapped exclusively to the JG cells of theGsa-deficient animals. Progressive albuminuria occurred in Gsa-deficient mice. Compared with controls expressing wild-type Gsa alleles, the Gsa-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gsa-deficient animals featured endothelial gaps, thickened basement membrane, and fibrin-like intraluminal deposits, which are classic signsof thromboticmicroangiopathy.Additionally,wefound endothelialdamagein peritubular capillaries and vasa recta. Because deficiency of vascular endothelial growth factor (VEGF) results in thromboticmicroangiopathy, we addressed the possibility that Gsa knockout may result in impaired VEGF production.We detected VEGF expression in JG cells of control mice, and cAMP agonists regulated VEGF expression in cultured renin-producing cells. Ourdata demonstrate that Gsa deficiency in JGcells of adultmice results in kidney injury, and suggest that JGcells are critically involved in the maintenance and protection of the renal microvascular endothelium.