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

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• Bile acids are signaling molecules that activate farnesoid X receptor (FXR) and G protein-coupled receptor TGR5.
• FXR and TGR5 activation has shown renoprotective effects in diabetes and obesity-related kidney disease.
• The specific signaling pathways mediating these renoprotective effects require further elucidation.

Purpose of the Study:

• To investigate whether the renoprotective effects of FXR and TGR5 are mediated through differential or synergistic signaling pathways.
• To determine the therapeutic potential of dual FXR/TGR5 agonists in diabetic and obesity-related nephropathy.

Main Methods:

• Administration of the dual FXR/TGR5 agonist INT-767 to mice models of diabetes (streptozotocin-induced, type 2) and diet-induced obesity.
• Assessment of individual effects of selective FXR agonist (obeticholic acid, OCA) and TGR5 agonist (INT-777) in diabetic mice.
• Evaluation of renal function, histology, and molecular signaling pathways, including mitochondrial function and oxidative stress markers.

Main Results:

• The dual agonist INT-767 significantly improved proteinuria and prevented kidney damage (podocyte injury, mesangial expansion, tubulointerstitial fibrosis) in diabetic mice.
• INT-767 modulated distinct renal signaling pathways, including activating the AMPK/SIRT1/PGC-1α cascade, inhibiting endoplasmic reticulum stress, and normalizing renal lipid metabolism.
• In diet-induced obesity models, INT-767 prevented mitochondrial dysfunction and oxidative stress.

Conclusions:

• FXR and TGR5 activation by INT-767 exerts coordinated, renoprotective effects in models of diabetic nephropathy and obesity-related kidney disease.
• INT-767 targets multiple critical pathways involved in kidney disease pathogenesis.
• The identified renal signaling pathways regulated by FXR and TGR5 represent promising therapeutic targets for treating nephropathy associated with diabetes and obesity.