FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity

J Am Soc Nephrol. 2018 Jan;29(1):118-137. doi: 10.1681/ASN.2017020222. Epub 2017 Oct 31.

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-1α, sirtuin 3, estrogen-related receptor-α, 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.

Keywords: diabetic nephropathy; metabolism; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Albuminuria / etiology
  • Animals
  • Bile Acids and Salts / pharmacology
  • Chenodeoxycholic Acid / analogs & derivatives
  • Chenodeoxycholic Acid / pharmacology
  • Cholesterol / metabolism
  • Cholic Acids / pharmacology
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control*
  • Disease Progression
  • Endoplasmic Reticulum Stress
  • Fibrosis
  • Glomerular Mesangium / pathology
  • Humans
  • Kidney Tubules / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mitochondria / metabolism
  • Obesity / complications
  • Obesity / metabolism*
  • Oxidative Stress
  • Podocytes / pathology
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects*
  • Triglycerides / metabolism

Substances

  • 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
  • 6alpha-ethyl-23(S)-methylcholic acid
  • Bile Acids and Salts
  • Cholic Acids
  • Gpbar1 protein, mouse
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, G-Protein-Coupled
  • Triglycerides
  • obeticholic acid
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid
  • Cholesterol