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Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney
Open accessAbstract
Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein-coupled metabolic receptor, GPR91, in the glomerular endothelium as observed in rat, mouse, and rabbit kidney sections. Elements of signal transduction included endothelial Ca2+, the production of NO and prostaglandin (PGE2), and their paracrine actions on adjacent renin-producing cells. This GPR91 signaling cascade may serve to modulate kidney function and help remove metabolic waste products through renal hyperfiltration, and it could also link metabolic diseases, such as diabetes, or metabolic syndrome with RAS overactivation, systemic hypertension, and organ injury.
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“Moreover, the effects of Semax on the anticoagulant, fibrinolytic, and platelet components of the anticoagulation system were reported [91].”
From Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis (2021) · cites this paper as [91]
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Metadata
- Authors
- Toma, I., Kang, J. J., Sipos, A., Vargas, S., Bansal, E., Hanner, F., Meer, E., & Peti-Peterdi, J.
- Affiliations
- University of Southern California (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2008-06-01
- Volume
- 118
- Issue
- 7
- Pages
- 2526-34
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2413183
- OpenAlex
- W2125951881
- Cited by
- 322
- References
- 47
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 19 · 2023: 17 · 2022: 21 · 2021: 26 · 2020: 24 · 2019: 23 · 2018: 17 · 2017: 21 · 2016: 16 · 2015: 11 · 2014: 12 · 2013: 22 · 2012: 16
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 64324, DK37097, DK 74754, R01DK074754, R01DK037097, R01DK064324)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Renal and Vascular Pathologies
- Keywords
- GPR91, succinate receptor, renin secretion, high glucose, renin-angiotensin system, diabetes mellitus, kidney, glomerular endothelium, paracrine signaling, nitric oxide, prostaglandin E2, calcium signaling, hypertension, renal hyperfiltration, metabolic syndrome, end-stage renal disease
- MeSH terms
- Animals, Citrates, Diabetes Mellitus, Experimental, Female, Glucose, Hyperglycemia, Juxtaglomerular Apparatus, Kidney, Male, Malonates, Mice, Inbred C57BL, Mice, Transgenic, Nitric Oxide, Rabbits, Renin, Dinoprostone, Mice, Knockout, Succinic Acid, Paracrine Communication, Calcium Signaling, Endothelial Cells, Receptors, G-Protein-Coupled, Mice, Rats
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