Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage

Abstract

Intracellular cAMP, the production of which is catalyzed by the -subunit of the stimulatory G protein (Gs), 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 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-deficient animals. Progressive albuminuria occurred in Gs-deficient mice. Compared with controls expressing wild-type Gs alleles, the Gs-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gs-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 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 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.

How can juxtaglomerular renin-producing cells support the integrity of glomerular endothelial cells?

“…Although renin cells cannot repopulate damaged glomerular endothelial cells [7], they appear to exert a protective effect on endothelial cells. The article by Steglich and coworkers entitled "Renin cells with defective Gsα/cAMP-signaling contribute to renal endothelial damage" as published in this issue of Pflügers Archiv now confirms and extends previous findings that renin cells have also influence on the integrity of the glomerular endothelium [5]. The authors report that continuous disruption of cAMP signaling by renin cell-specific deletion of the Gsα protein downregulated renin expression as expected, but in addition also led to endothelial damage of glomerular capillaries as indicated by the change of morphological and genetic markers.…”

COX-2-derived PGE2 triggers hyperplastic renin expression and hyperreninemia in aldosterone synthase-deficient mice

“…These observations are in line with a more general renin inhibitory effect of COX-2 blockers, in particular in situations of a stimulated renin synthesis and secretion [ 18 , 25 , 64 ]. Since the cyclic AMP signaling pathway is the yet best characterized trigger for renin gene transcription and for renin secretion [ 33 , 35 , 54 ], we next looked for the existence of cAMP stimulatory prostanoid receptors in renin-expressing cells. Apart from prostacyclin receptors, the PGE 2 EP2 and EP4 receptors are the yet best established activators of adenylyl cyclase activity in target cells [ 12 , 55 ].…”

Serial intravital imaging captures dynamic and functional endothelial remodeling with single-cell resolution

“…Clonal GEnC proliferation at the glomerular vascular pole under diabetic conditions found in the present study ( Supplemental Figure 3 ) is consistent with the classic renal histopathological finding in human diabetic patients, the proliferation and growth of aberrant blood vessels at the glomerular vascular pole ( 38 ). Interestingly, renin cell–derived angiogenic factors, including VEGF, have been recently identified ( 39 , 40 ). It is also known that endothelial cell fenestrations, which are typical for GEnCs, begin in the renin + AA segment ( 41 ).…”