Interference with Gs<i>α</i>-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage.

Abstract

Intracellular cAMP, the production of which is catalyzed by the <i>α</i>-subunit of the stimulatory G protein (Gs<i>α</i>), 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 of Gs<i>α</i> in JG cells and monitored them for 6 months after induction at 6 weeks of age. The knockout mapped exclusively to the JG cells of the Gs<i>α</i>-deficient animals. Progressive albuminuria occurred in Gs<i>α</i>-deficient mice. Compared with controls expressing wild-type Gs<i>α</i> alleles, the Gs<i>α</i>-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gs<i>α</i>-deficient animals featured endothelial gaps, thickened basement membrane, and fibrin-like intraluminal deposits, which are classic signs of thrombotic microangiopathy. Additionally, we found endothelial damage in peritubular capillaries and vasa recta. Because deficiency of vascular endothelial growth factor (VEGF) results in thrombotic microangiopathy, we addressed the possibility that Gs<i>α</i> 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. Our data demonstrate that Gs<i>α</i> deficiency in JG cells of adult mice results in kidney injury, and suggest that JG cells are critically involved in the maintenance and protection of the renal microvascular endothelium.