G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases

Hu, Jianyan; Li, Tingting; Du, Xin; Wu, Qiang; Le, Yun-Zheng

doi:10.1016/j.visres.2017.05.001

Cited by 19 publications

(9 citation statements)

References 66 publications

(112 reference statements)

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“…Thus, when succinate is oxidized to fumarate, FAD is reduced and electrons are channeled to ubiquinone through SDH [48] . Inhibition of SDH activity and the associated accumulation of succinate is observed in response to ischemia [11] , hypoxia [49] , and hyperglycemia [15] , and the accompanying GPR91-induced responses are linked with beneficial tissue adaptation to hypoxia/ischemia such as VEGF production in brain and retina [13] , [50] , cardiac hypertrophy [51] , hepatic stellate cell transdifferentiation [4] , and renin release [9] . However, when the succinate accumulation and GPR91 stimulation becomes more chronic, as for example in response to hyperglycemia in diabetic patients [15] , these effects become harmful.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, several of the classical rodent models of metabolic dysfunction have all displayed elevated plasma levels of succinate [7] , a finding also established in patients suffering from Type 2 diabetes (T2D) [12] . GPR91 has been proposed to be involved in the development of diabetes complications including neuronal VEGF-mediated neovascularization in diabetic retinopathy [3] , [13] , [14] as well as in diabetic nephropathy [9] , [15] . Adipocytes also express GPR91 and activation of the receptor inhibits lipolysis [16] .…”

Section: Introductionmentioning

confidence: 99%

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Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

Trauelsen

Ulven

Hjorth

et al. 2017

Molecular Metabolism

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ObjectiveBesides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools.Methods and resultsHere we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase.ConclusionsThese novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

Trauelsen

Ulven

Hjorth

et al. 2017

Molecular Metabolism

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“…Overall, these correlations although compelling are not definitive proof that activated leukocytes, and by inference a background of inflammation, are the cause of the retinal non-perfusion and ischemia in diabetes and MS. Ischemic retina is widely accepted as a source of VEGF, either from retinal cells such as Müller cells ( 164 ) and ganglion cells ( 165 ) or from the activated leukocytes themselves ( 166 ). It is also possible that the activated leukocytes induce Müller cell production of VEGF ( 167 ).…”

Section: Diabetic Retinopathy Is An Inflammatory Diseasementioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5 + CD11b + monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

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“…GPR91 is also expressed in ganglion cells of the retina. During the development of diabetic retinopathy, succinate levels increase in the retina, activating GPR91 and up-regulating VEGF signaling [ 137 ] which plays a central role in mediating microvascular and macrovascular pathology in diabetes.…”

Section: Biochemistry Of Mitochondrial Ageingmentioning

confidence: 99%

Intimate Relations—Mitochondria and Ageing

Webb¹,

Sideris²

2020

IJMS

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Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. We review the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction.

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G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases

Cited by 19 publications

References 66 publications

Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

The Role of Inflammation in Diabetic Retinopathy

Intimate Relations—Mitochondria and Ageing

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