| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Wang, Xiaoxin X. Edelstein, Michal Herman Gafter, Uzi Qiu, Liru Luo, Yuhuan Dobrinskikh, Evgenia Lucia, Scott Adorini, Luciano D'Agati, Vivette D. Levi, Jonathan Rosenberg, Avi Kopp, Jeffrey B. Gius, David R. Saleem, Moin A. Levi, Moshe |
| Description |
Author Affiliation: Wang XX ( Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado); Edelstein MH ( Rabin Medical Center, Department of Nephrology and Hypertension); Gafter U ( Rabin Medical Center, Department of Nephrology and Hypertension); Qiu L ( Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado); Luo Y ( Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado); Dobrinskikh E ( Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado); Lucia S ( Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado); Adorini L ( Intercept, New York, New York); D'Agati VD ( Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York); Levi J ( National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland); Rosenberg A ( National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland); Kopp JB ( National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland); Gius DR ( Northwestern University Feinberg School of Medicine, Chicago, Illinois); Saleem MA ( University of Bristol, Southmead Hospital, Bristol, United Kingdom.); Levi M ( Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado) |
| 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 $H_{2}O_{2}$ generation and increased the activity of SOD2, which associated with decreased urinary levels of $H_{2}O_{2}$ 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. |
| File Format |
HTM / HTML |
| ISSN |
10466673 |
| e-ISSN |
15333450 |
| Journal |
Journal of the American Society of Nephrology |
| Issue Number |
5 |
| Volume Number |
27 |
| Language |
English |
| Publisher |
American Society of Nephrology |
| Publisher Date |
2016-05-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Nephrology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Nephrology |
