G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in
Obesity and Diabetes.
Authors Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, Lucia S, Adorini
L, D'Agati VD, Levi J, Rosenberg A, Kopp JB, Gius DR, Saleem MA, Levi M
Submitted By Moshe Levi on 11/9/2015
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2015
Date Published 9/1/2015
Volume : Pages Not Specified : Not Specified
PubMed Reference 26424786
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 ß-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
ß-oxidation. Compared with normal kidney biopsy specimens, kidney specimens from
patients with established ORG or DN expressed significantly more TGR5 mRNA, and
levels 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.