TY - JOUR
T1 - FXR/TGR5 dual agonist prevents progression of nephropathy in diabetes and obesity
AU - Wang, Xiaoxin X.
AU - Wang, Dong
AU - Luo, Yuhuan
AU - Myakala, Komuraiah
AU - Dobrinskikh, Evgenia
AU - Rosenberg, Avi Z.
AU - Levi, Jonathan
AU - Kopp, Jeffrey B.
AU - Field, Amanda
AU - Hill, Ashley
AU - Lucia, Scott
AU - Qiu, Liru
AU - Jiang, Tao
AU - Peng, Yingqiong
AU - Orlicky, David
AU - Garcia, Gabriel
AU - Herman-Edelstein, Michal
AU - D’Agati, Vivette
AU - Henriksen, Kammi
AU - Adorini, Luciano
AU - Pruzanski, Mark
AU - Xie, Cen
AU - Krausz, Kristopher W.
AU - Gonzalez, Frank J.
AU - Ranjit, Suman
AU - Dvornikov, Alexander
AU - Gratton, Enrico
AU - Levi, Moshe
N1 - Publisher Copyright:
Copyright © 2018 by the American Society of Nephrology.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85036622151&partnerID=8YFLogxK
U2 - 10.1681/asn.2017020222
DO - 10.1681/asn.2017020222
M3 - Article
C2 - 29089371
AN - SCOPUS:85036622151
SN - 1046-6673
VL - 29
SP - 118
EP - 137
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 1
ER -