title: G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes.
abstract: 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 β-oxidation, including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), and Nrf-1. Increased activity of SIRT3 was evidenced by normalization of the increased acetylation of mitochondrial 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 mitochondrial biogenesis, decreased oxidative stress, and increased fatty acid β-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.
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Xiaoxin.Wang@ucdenver.edu Moshe.Levi@ucdenver.edu.
authors.forename: Xiaoxin X
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Rabin Medical Center, Department of Nephrology and Hypertension; Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Israel;
authors.forename: Michal Herman
authors.initials: MH
authors.lastname: Edelstein
authors.affiliation: Rabin Medical Center, Department of Nephrology and Hypertension; Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Israel;
authors.forename: Uzi
authors.initials: U
authors.lastname: Gafter
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Liru
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Evgenia
authors.initials: E
authors.lastname: Dobrinskikh
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Scott
authors.initials: S
authors.lastname: Lucia
authors.affiliation: Intercept, New York, New York;
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.affiliation: Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York;
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Levi
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
authors.forename: Avi
authors.initials: A
authors.lastname: Rosenberg
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.
authors.forename: David R
authors.initials: DR
authors.lastname: Gius
authors.affiliation: University of Bristol, Southmead Hospital, Bristol, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Xiaoxin.Wang@ucdenver.edu Moshe.Levi@ucdenver.edu.
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts; D002793:Cholic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000517:prevention & control*; D006801:Humans; D006861:Hydrogen Peroxide; D007674:Kidney Diseases / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications*; D018384:Oxidative Stress; D050199:Podocytes; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
chemical_list: D001647:Bile Acids and Salts; D002793:Cholic Acids; D006861:Hydrogen Peroxide; D043562:Receptors, G-Protein-Coupled; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C545501:6alpha-ethyl-23(S)-methylcholic acid; C513561:Gpbar1 protein, mouse
keywords: diabetic nephropathy; metabolism; mitochondria; obesity; oxidative stress