G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes
G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes
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DOI：
10.1681/asn.2014121271
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发表时间：
2016-05-01
影响因子：
13.6
通讯作者：
Levi, Moshe
中科院分区：
文献类型：
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作者：
Wang, Xiaoxin X.;Edelstein, Michel Herman;Levi, Moshe
肥胖和糖尿病是肾脏疾病的主要原因。在这项研究中，我们确定了 G 蛋白偶联胆汁酸受体 TGR5 在肥胖相关肾小球病 (ORG) 和糖尿病肾病 (DN) 中的调节和作用，此前研究表明该受体受高葡萄糖和/或脂肪酸的调节。用选择性 TGR5 激动剂 INT-777 治疗糖尿病 db/db 小鼠可减少蛋白尿、足细胞损伤、系膜扩张、纤维化和肾脏中 CD68 巨噬细胞浸润。 INT-777 还诱导线粒体生物发生的主要调节因子、氧化应激抑制剂和脂肪酸 β-氧化诱导剂的肾脏表达，包括 Sirtuin 1 (SIRT1)、sirtuin 3 (SIRT3) 和 Nrf-1。线粒体乙酰化增加的正常化证明了 SIRT3 活性的增加！在未经治疗的 db/db 小鼠中观察到超氧化物歧化酶 2 (SOD2) 和异柠檬酸脱氢酶 2 (IDH2)。因此，INT-777 减少了线粒体 H2O2 的产生并增加了 SOD2 的活性，这与尿中 H2O2 和硫代巴比妥酸反应物质水平的降低有关。此外，INT-777 降低了肾脏脂质积累。 INT-777 还可以预防饮食引起的肥胖小鼠的肾脏疾病。在高葡萄糖培养的人类足细胞中，INT-777 诱导线粒体！生物发生、氧化应激减少和脂肪酸β-氧化增加。与正常肾活检标本相比，已确诊 ORG 或 DN 患者的肾脏标本表达的 TGR5 mRNA 显着减少，且水平与疾病进展呈负相关。我们的结果表明，TGR5 激活可诱导线粒体生物发生并防止肾脏氧化应激和脂质积累，从而确定 TGR5 在抑制肥胖和糖尿病肾病中的作用。
Obesity and diabetes mellitus are the leading causes of renal disease. In this study, we determined the regulation and role of the G protein-coupled bile acid receptor TGR5, previously shown to be regulated by high glucose and/or fatty acids, in obesity-related glomerulopathy (ORG) and diabetic nephropathy (DN). Treatment of diabetic db/db mice with the selective TGR5 agonist INT-777 decreased proteinuria, podocyte injury, mesangial expansion, fibrosis, and CD68 macrophage infiltration in the kidney. INT-777 also induced renal expression of master regulators of mitochondrial biogenesis, inhibitors of oxidative stress, and inducers of fatty acid beta-oxidation, including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), and Nrf-1. Increased activity of SIRT3 was evidenced by normalization of the increased acetylation of mitochondria! superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2) observed in untreated db/db mice. Accordingly, INT-777 decreased mitochondrial H2O2 generation and increased the activity of SOD2, which associated with decreased urinary levels of H2O2 and thiobarbituric acid reactive substances. Furthermore, INT-777 decreased renal lipid accumulation. INT-777 also prevented kidney disease in mice with diet induced obesity. In human podocytes cultured with high glucose, INT-777 induced mitochondria! biogenesis, decreased oxidative stress, and increased fatty acid beta-oxidation. Compared with normal kidney biopsy specimens, kidney specimens from patients with established ORG or DN expressed significantly less TGR5 mRNA, and levels inversely correlated with disease progression. Our results indicate that TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation, establishing a role for TGR5 in inhibiting kidney disease in obesity and diabetes.