Amelioration of diabetic nephropathy using a retinoic acid receptor B2 agonist Academic Article uri icon

Overview

MeSH Major

  • Benzoates
  • Hepatic Stellate Cells
  • Non-alcoholic Fatty Liver Disease
  • Receptors, Retinoic Acid
  • Thiazoles

abstract

  • Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Vitamin A (VA) and its derivatives, known as retinoids, play critical roles in renal development through retinoic acid receptor b2 (RARb2). Disruptions in VA signaling pathways are associated with the onset of diabetic nephropathy (DN). Despite the known role of RARb2 in renal development, the effects of selective agonists for RARb2 in a high-fat diet (HFD) model of DN are unknown. Here we examined whether AC261066 (AC261), a highly selective agonist for RARb2, 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 1 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 1 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 a-smooth muscle actin (a-SMA) and type IV collagen (Col-IV) was lower in HFD 1 AC261–treated mice compared with HFD alone. Ultrastructural and immunohistochemistry analyses showed that, compared with HFD-fed mice, HFD 1 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.

publication date

  • October 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1124/jpet.118.249375

PubMed ID

  • 30054312

Additional Document Info

start page

  • 82

end page

  • 94

volume

  • 367

number

  • 1