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FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and
Authors Wang XX, Wang D, Luo Y, Myakala K, Dobrinskikh E, Rosenberg AZ, Levi J, Kopp JB,
Field A, Hill A, Lucia S, Qiu L, Jiang T, Peng Y, Orlicky D, Garcia G,
Herman-Edelstein M, D'Agati V, Henriksen K, Adorini L, Pruzanski M, Xie C,
Krausz KW, Gonzalez FJ, Ranjit S, Dvornikov A, Gratton E, Levi M
Submitted By Moshe Levi on 11/8/2017
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2017
Date Published 10/1/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference 29089371
Abstract Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor
(FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5
have renoprotective roles in diabetes- and obesity-related kidney disease. Here,
we determined whether these effects are mediated through differential or
synergistic signaling pathways. We administered the FXR/TGR5 dual agonist
INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with
type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity. We also
examined the individual effects of the selective FXR agonist obeticholic acid
(OCA) and the TGR5 agonist INT-777 in diabetic mice. The FXR agonist OCA and the
TGR5 agonist INT-777 modulated distinct renal signaling pathways involved in the
pathogenesis and treatment of diabetic nephropathy. Treatment of diabetic DBA/2J
and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and
prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis.
INT-767 exerted coordinated effects on multiple pathways, including stimulation
of a signaling cascade involving AMP-activated protein kinase, sirtuin 1,
PGC-1a, sirtuin 3, estrogen-related receptor-a, and Nrf-1; inhibition of
endoplasmic reticulum stress; and inhibition of enhanced renal fatty acid and
cholesterol metabolism. Additionally, in mice with diet-induced obesity, INT-767
prevented mitochondrial dysfunction and oxidative stress determined by
fluorescence lifetime imaging of NADH and kidney fibrosis determined by second
harmonic imaging microscopy. These results identify the renal signaling pathways
regulated by FXR and TGR5, which may be promising targets for the treatment of
nephropathy in diabetes and obesity.