Role of the retinoic acid receptor-α in HIV-associated nephropathy

All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-alpha (RAR alpha). Here, we report that Am580, a water-soluble RAR alpha-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Furthermore, RAR alpha-/- Tg26 mice developed more severe kidney and podocyte injury than did RAR alpha-/- Tg26 mice. Am580 failed to ameliorate kidney injury in RAR alpha-/- Tg26 mice, confirming our hypothesis that Am580 acts through RAR alpha. Although the expression of RAR alpha-target genes was suppressed in the kidneys of Tg26 mice and of patients with HIVAN, the expression of RAR alpha in the kidney was not different between patients with HIVAN and minimal change disease. However, the tissue levels of retinoic acid were reduced in the kidney cortex and isolated glomeruli of Tg26 mice. Consistent with this, the expression of two key enzymes in the retinoic acid synthetic pathway, retinol dehydrogenase type 1 and 9, and the overall enzymatic activity for retinoic acid synthesis were significantly reduced in the glomeruli of Tg26 mice. Thus, a defect in the endogenous synthesis of retinoic acid contributes to loss of the protection by retinoic acid in HIVAN. Hence, RAR alpha agonists may be potential agents for the treatment of HIVAN. Kidney International (2011) 79, 624-634; doi: 10.1038/ki.2010.470; published online 8 December 2010