G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes

Xiaoxin X. Wang*, Michal Herman Edelstein, Uzi Gafter, Liru Qiu, Yuhuan Luo, Evgenia Dobrinskikh, Scott Lucia, Luciano Adorini, Vivette D. D'Agati, Jonathan Levi, Avi Rosenberg, Jeffrey B. Kopp, David R. Gius, Moin A. Saleem, Moshe Levi

*Corresponding author for this work

Research output: Contribution to journalArticle

46 Scopus citations

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 b-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 dietinduced obesity. In human podocytes cultured with high glucose, INT-777 induced mitochondrial biogenesis, decreased oxidative stress, and increased fatty acid b-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.

Original languageEnglish (US)
Pages (from-to)1362-1378
Number of pages17
JournalJournal of the American Society of Nephrology
Volume27
Issue number5
DOIs
StatePublished - May 2016

ASJC Scopus subject areas

  • Nephrology

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    Wang, X. X., Edelstein, M. H., Gafter, U., Qiu, L., Luo, Y., Dobrinskikh, E., Lucia, S., Adorini, L., D'Agati, V. D., Levi, J., Rosenberg, A., Kopp, J. B., Gius, D. R., Saleem, M. A., & Levi, M. (2016). G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes. Journal of the American Society of Nephrology, 27(5), 1362-1378. https://doi.org/10.1681/ASN.2014121271