Studies on renin release from isolated superfused glomeruli: effects of temperature, urea, ouabain and ethacrynic acid.

Baumbach, L; Leyssac, P. P.; Skinner, Sandford L.

doi:10.1113/jphysiol.1976.sp011417

Cited by 38 publications

(28 citation statements)

References 24 publications

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“…5a), which is consistent with a previous report that succinate-treated kidney cultures ex vivo released renin 11 . Renin is a key enzyme in the renin-angiotensin system, which is essential in blood pressure regulation 12,13 .…”

supporting

confidence: 82%

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

Miao²,

Lin³

et al. 2004

Nature

762

832

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The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism 1 . Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations 2 . The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/ extrusion. Here we show that GPR91 (ref.3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to a-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and a-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure 5,6 .In a search for natural ligands for orphan GPCRs, we tested extracts from various animal tissues for their ability to evoke an increase in intracellular Ca 2þ concentration ([Ca 2þ ] i ) using the aequorin assay 7 . We found that fractions from pig kidney extracts specifically activated cells expressing GPR91 (Fig. 1a). GPR91 is an orphan GPCR highly expressed in the kidney and shares 33% amino acid identity with GPR99/GPR80 (refs 4, 8). On the basis of their homology with the purinergic receptor P2Y1, nucleotide ligands were predicted for GPR91 and GPR99 (ref. 4). However, the GPR91 ligand activity in pig kidney extracts was resistant to various stringent treatments including alkaline phosphatase, peptidase, and hydrolysis in 6 M HCl at 100 8C. Accordingly, the supposition that GPR91 might be activated by a nucleotide or peptide ligand was unlikely. We purified the natural ligand for GPR91 by ion-exchange, size-exclusion and reversed-phase fast performance liquid chromatography/high-performance liquid chromatography (Fig. 1a).A major molecular ion [M þ H] þ at m/z 119.2 was observed by mass spectrometry (Fig. 1b). 1 H NMR analysis revealed a single type of proton in the highly purified GPR91 ligand (Fig. 1c). 13 C NMR analysis further suggested the presence of -CH 2 -(methylene) and ¼C¼O (carbonyl) groups (Fig. 1d). Combined with mass spectrometry results and the biochemical properties of the ligand, the purified GPR91 ligand was predicted and confirmed to be succinic acid (Fig. 1c, d).Commercially obtained succinate (the physiological form of succinic acid) increased [Ca 2þ ] i dose-dependently in the aequorin assay (Fig. 2a). Succinate also activated mouse and rat orthologues of GPR91 (Fig. 2a). The succinate-induced increase in [Ca 2þ ] i was further confirmed with a fluorimetric imaging plate reader (FLIPR) system in the 293-hGP...

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supporting

confidence: 82%

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

Miao²,

Lin³

et al. 2004

Nature

762

832

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“…Kidneys express both GPR91 and GPR99 (refs 7, 8), and He et al provide compelling evidence that, via GPR91, succinate stimulates the release of renin from the kidneys. This reveals the mechanism behind the earlier observation that succinate increases the release of renin from isolated kidney capillaries 9 . Renin is part of the reninangiotensin system (RAS) -a series of enzymes and molecules that culminate in the production of the eight-amino-acid peptide angiotensin II.…”

mentioning

confidence: 70%

Orphan detectors of metabolism

Hebert

2004

Nature

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“…In 1976, succinate was shown to induce renin release in isolated rat glomeruli while evaluating its role as an energy substrate (Baumbach et al, 1976). The mechanism for this effect was partially elucidated via the identification of its membrane receptor.…”

Section: Regulation Of Blood Pressurementioning

confidence: 99%

Insight into SUCNR1 (GPR91) structure and function

Gilissen

Jouret

Pirotte

et al. 2016

Pharmacology & Therapeutics

110

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SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate.According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy.The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

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Studies on renin release from isolated superfused glomeruli: effects of temperature, urea, ouabain and ethacrynic acid.

Cited by 38 publications

References 24 publications

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

Orphan detectors of metabolism

Insight into SUCNR1 (GPR91) structure and function

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