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Amelioration of Diabetic Nephropathy Using a Retinoic Acid Receptor β2 Agonist
Steven E Trasino1, Xiao-Han Tang1, Maria M Shevchuk1
1Departments of Pharmacology (S.E.T., X.-H.T., L.J.G.) and Pathology (M.M.S.) and Division of Nephrology and Hypertension, Department of Medicine (M.E.C.), Weill Cornell Medical College of Cornell University, School of Urban Public Health, Nutrition Program, Hunter College, City University of New York (S.E.T.), and NewYork-Presbyterian Hospital-Weill Cornell Medical Center (M.E.C.), New York, New York.
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 with HFD-fed mice, HFD + AC261-treated mice had improved glycemic control and reductions in proteinuria and urine albumin-to-creatinine ratio. Several cellular hallmarks of DN were mitigated in HFD + AC261-treated mice, including reductions in tubule lipid droplets, podocyte (POD) effacement, endothelial cell collapse, mesangial expansion, and glomerular basement membrane 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 with HFD alone. Ultrastructural and immunohistochemistry analyses showed that, compared with 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 Wilms tumor-suppressor gene 1 in PODs. Given the need for novel DN therapies, our results warrant further studies of the therapeutic properties of AC261 in DN.
Insights
A novel drug, AC261066 (AC261), targeting retinoic acid receptor beta2 (RARβ2), shows promise in treating diabetic nephropathy (DN). AC261 improved kidney function and reduced disease markers in a high-fat diet mouse model.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Vitamin A (VA) and its derivatives (retinoids) are crucial for kidney development via retinoic acid receptor beta2 (RARβ2).
- Dysregulated VA signaling contributes to diabetic nephropathy (DN) development.
- The therapeutic potential of selective RARβ2 agonists in DN remains unexplored.
Purpose of the Study:
- To investigate the therapeutic efficacy of AC261066 (AC261), a selective RARβ2 agonist, in a high-fat diet (HFD)-induced mouse model of DN.
- To assess the impact of AC261 on glycemic control, kidney function, and cellular hallmarks of DN.
Main Methods:
- C57BL/6 mice were fed a high-fat diet (HFD) and treated with AC261 for 12 weeks.
- Evaluated glycemic control, proteinuria, urine albumin-to-creatinine ratio, and histological/ultrastructural changes in kidney tissues.
- Assessed expression of myofibroblast markers (α-SMA, Col-IV) and podocyte-specific proteins (podocin, WT1).
Main Results:
- AC261 treatment was well-tolerated in HFD-fed mice.
- HFD + AC261 mice exhibited improved glycemic control, reduced proteinuria, and lower albuminuria compared to HFD-only mice.
- AC261 mitigated key DN pathologies including lipid droplets, podocyte effacement, endothelial cell collapse, mesangial expansion, and GBM thickening.
- Reduced myofibroblast markers and preserved podocyte structure and protein levels were observed in AC261-treated mice.
Conclusions:
- AC261 demonstrates significant therapeutic potential in ameliorating DN in a preclinical HFD model.
- The drug improved kidney function and protected against cellular damage in DN.
- Further investigation into AC261 as a novel therapeutic agent for DN is warranted.
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