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AdipoRon, adiponectin receptor agonist, improves vascular function in the mesenteric arteries of type 2 diabetic mice.

ABSTRACT: BACKGROUND:An orally active synthetic adiponectin receptor agonist, AdipoRon has been suggested to ameliorate insulin resistance, and glucose tolerance. However, the chronic effect of AdipoRon in the vascular dysfunction in type 2 diabetes has not been studied yet. Thus, in this study, we examined whether AdipoRon improves vascular function in type 2 diabetes. METHODS:Type 2 diabetic (db-/db-) mice were treated with AdipoRon (10 mg/kg/everyday, by oral gavage) for 2 weeks. Body weight and blood glucose levels were recorded every other day during the experimental period. Diameter of mesenteric arteries was measured. And western blot analysis was performed with mesenteric arteries. RESULTS:Pressure-induced myogenic response was significantly increased while endothelium-dependent relaxation was reduced in the mesenteric arteries of db-/db- mice. Treatment of AdipoRon normalized potentiated myogenic response, whereas endothelium-dependent relaxation was not affected by treatment of AdipoRon. The expression levels of AdiR1, AdiR2, APPL1, and APPL 2 were increased in the mesenteric arteries of db-/db- mice and treatment of AdipoRon did not affect them. Interestingly, AdipoRon treatment increased the phospho-AMPK and decreased MYPT1 phosphorylation in db-/db- mice while there was no change in the level of eNOS phosphorylation. CONCLUSION:The treatment of AdipoRon improves vascular function in the mesenteric arteries of db-/db- mice through endothelium-independent mechanism. We suggest that MLCP activation through reduced phosphorylation of MYPT1 might be the dominant mechanism in the AdipoRon-induced vascular effect.

SUBMITTER: Choi SK

PROVIDER: S-EPMC7077821 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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AdipoRon, adiponectin receptor agonist, improves vascular function in the mesenteric arteries of type 2 diabetic mice.

Choi Soo-Kyoung SK Kwon Youngin Y Byeon Seonhee S Haam Chae Eun CE Lee Young-Ho YH

PloS one 20200317 3

<h4>Background</h4>An orally active synthetic adiponectin receptor agonist, AdipoRon has been suggested to ameliorate insulin resistance, and glucose tolerance. However, the chronic effect of AdipoRon in the vascular dysfunction in type 2 diabetes has not been studied yet. Thus, in this study, we examined whether AdipoRon improves vascular function in type 2 diabetes.<h4>Methods</h4>Type 2 diabetic (db-/db-) mice were treated with AdipoRon (10 mg/kg/everyday, by oral gavage) for 2 weeks. Body we ...[more]

PMID: 32182257

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Project description:Background3',4'-Dihydroxyflavonol (DiOHF) is an effective antioxidant that acutely preserves nitric oxide (NO) activity in the presence of elevated reactive oxygen species (ROS). We hypothesized that DiOHF treatment (7 days, 1 mg/kg per day s.c.) would improve relaxation in mesenteric arteries from diabetic rats where endothelial dysfunction is associated with elevated oxidant stress.Methodology/principal findingsIn mesenteric arteries from diabetic rats there was an increase in ROS, measured by L-012 and 2',7'-dichlorodihydrofluorescein diacetate fluorescence. NADPH oxidase-derived superoxide levels, assayed by lucigenin chemiluminescence, were also significantly increased in diabetic mesenteric arteries (diabetes, 4892±946 counts/mg versus normal 2486±344 counts/mg, n = 7-10, p<0.01) associated with an increase in Nox2 expression but DiOHF (2094±300 counts/mg, n = 10, p<0.001) reversed that effect. Acetylcholine (ACh)-induced relaxation of mesenteric arteries was assessed using wire myography (pEC(50) = 7.94±0.13 n = 12). Diabetes significantly reduced the sensitivity to ACh and treatment with DiOHF prevented endothelial dysfunction (pEC(50), diabetic 6.86±0.12 versus diabetic+DiOHF, 7.49±0.13, n = 11, p<0.01). The contribution of NO versus endothelium-derived hyperpolarizing factor (EDHF) to ACh-induced relaxation was assessed by evaluating responses in the presence of TRAM-34+apamin+iberiotoxin or N-nitro-L-arginine+ODQ respectively. Diabetes impaired the contribution of both NO (maximum relaxation, R(max) diabetic 24±7 versus normal, 68±10, n = 9-10, p<0.01) and EDHF (pEC(50), diabetic 6.63±0.15 versus normal, 7.14±0.12, n = 10-11, p<0.01) to endothelium-dependent relaxation. DiOHF treatment did not significantly affect the EDHF contribution but enhanced NO-mediated relaxation (R(max) 69±6, n = 11, p<0.01). Western blotting demonstrated that diabetes also decreased expression and increased uncoupling of endothelial NO synthase (eNOS). Treatment of the diabetic rats with DiOHF significantly reduced vascular ROS and restored NO-mediated endothelium-dependent relaxation. Treatment of the diabetic rats with DiOHF also increased eNOS expression, both in total and as a dimer.Conclusions/significanceDiOHF improves NO activity in diabetes by reducing Nox2-dependent superoxide production and preventing eNOS uncoupling to improve endothelial function.

Project description:Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor-? (PPAR?) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase-? (CaMKK?) and numbers of phosphorylated liver kinase B1 (LKB1)- and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKK?, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPAR? expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose-treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKK?/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPAR? pathway and downstream signaling, thus decreasing high-glucose-induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPAR? pathway, suggesting its efficacy for treating type 2 diabetes-associated DN.

Project description:Aims/hypothesisChronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist.MethodsWild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration.ResultsIn HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1β (51%, p < 0.001) and TGFβ (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-κB-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNFα (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1β, IL-18, IL-6 and IL-10.Conclusions/interpretationAdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.

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AdipoRon, adiponectin receptor agonist, improves vascular function in the mesenteric arteries of type 2 diabetic mice.

Publications

AdipoRon, adiponectin receptor agonist, improves vascular function in the mesenteric arteries of type 2 diabetic mice.

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