FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity
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 fluo...
Source: Journal of the American Society of Nephrology : JASN - Category: Urology & Nephrology Authors: Wang, X. X., Wang, D., Luo, Y., Myakala, K., Dobrinskikh, E., Rosenberg, A. Z., Levi, J., Kopp, J. B., Field, A., Hill, A., Lucia, S., Qiu, L., Jiang, T., Peng, Y., Orlicky, D., Garcia, G., Herman-Edelstein, M., DAgati, V., Henriksen, K., Adorini, L., Pru Tags: Basic Research Source Type: research
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