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

Lachmann, Peter; Hickmann, Linda; Steglich, Anne; Al-Mekhlafi, Moath; Gerlach, Michael; Jetschin, Niels; Jahn, Steffen; Hamann, Brigitte; Wnuk, Monika; Madsen, Kirsten; Djonov, Valentin; Chen, Min; Weinstein, Lee S; Hohenstein, Bernd; Hugo, Christian P M; Todorov, Vladimir T (2017). Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage. Journal of the American Society of Nephrology, 28(12), pp. 3479-3489. Lippincott Williams & Wilkins 10.1681/ASN.2017020173

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

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy 04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy
UniBE Contributor:	Wnuk, Monika, Djonov, Valentin Georgiev
Subjects:	600 Technology > 610 Medicine & health
ISSN:	1046-6673
Publisher:	Lippincott Williams & Wilkins
Language:	English
Submitter:	David Christian Haberthür
Date Deposited:	17 Jan 2018 13:10
Last Modified:	05 Dec 2022 15:09
Publisher DOI:	10.1681/ASN.2017020173
PubMed ID:	28775003
Uncontrolled Keywords:	Cell Signaling Pathophysiology of Renal Disease and Progression VEGF endothelium glomerulopathy renin angiotensin system
URI:	https://boris.unibe.ch/id/eprint/109002