Abstract
Vitamin A (VA) and its derivatives, known as retinoids, play critical roles in renal development through retinoic acid receptor β2 (RARβ2). Disruptions in VA signaling pathways are associated with the onset of diabetic nephropathy (DN). Despite the known role of RARβ2 in renal development, the effects of selective agonists for RARβ2 in a high fat diet (HFD) model of DN are unknown. Here we examined whether AC261066 (AC261), a highly selective agonist for RARβ2, exhibited therapeutic effects in a HFD model of DN in C57BL/6 mice. Twelve weeks of AC261 administration to HFD-fed mice was well-tolerated, with no observable side effects. Compared to HFD-fed mice, HFD+AC261 treated mice had improved glycemic control and reductions in proteinuria and urine albumin to creatinine ratio (ACR). A number of cellular hallmarks of DN were mitigated in HFD+AC261 treated mice, including reductions in tubule lipid droplets (LDs), podocyte (POD) effacement, endothelial cell (EC) collapse, mesangial expansion, and glomerular basement membrane (GBM) thickening. Mesangial and tubule interstitial expression of the myofibroblast markers α-smooth muscle actin (α-SMA) and type IV collagen (Col-IV) was lower in HFD+AC261 treated mice compared to HFD alone. Ultrastructural and immunohistochemistry (IHC) analyses showed that, compared to HFD-fed mice, HFD+AC261 treated mice showed preservation of POD foot process and slit diaphragm morphology, an increase in the levels of slit-diagram protein podocin and the transcription factor WT1 in PODs. Given the need for novel DN therapies, our results warrant further studies of the therapeutic properties of AC261 in DN.
- The American Society for Pharmacology and Experimental Therapeutics