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

Kidney Int. 2011 Mar;79(6):624-634. doi: 10.1038/ki.2010.470. Epub 2010 Dec 8.


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-α (RARα). Here, we report that Am580, a water-soluble RARα-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Furthermore, RARα-/- Tg26 mice developed more severe kidney and podocyte injury than did RARα+/- Tg26 mice. Am580 failed to ameliorate kidney injury in RARα-/- Tg26 mice, confirming our hypothesis that Am580 acts through RARα. Although the expression of RARα-target genes was suppressed in the kidneys of Tg26 mice and of patients with HIVAN, the expression of RARα 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, RARα agonists may be potential agents for the treatment of HIVAN.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AIDS-Associated Nephropathy / genetics
  • AIDS-Associated Nephropathy / metabolism*
  • AIDS-Associated Nephropathy / pathology
  • AIDS-Associated Nephropathy / prevention & control
  • AIDS-Associated Nephropathy / virology
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Benzoates / pharmacology
  • Cell Differentiation
  • Cell Proliferation
  • Disease Models, Animal
  • Female
  • Glomerulonephritis / metabolism
  • Glomerulonephritis / prevention & control
  • Glomerulonephritis / virology
  • HIV-1 / genetics*
  • Humans
  • Hydroxysteroid Dehydrogenases / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Podocytes / drug effects
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Podocytes / virology
  • Proteinuria / metabolism
  • Proteinuria / prevention & control
  • Proteinuria / virology
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / deficiency
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Retinoic Acid Receptor alpha
  • Retinoids / metabolism
  • Severity of Illness Index
  • Signal Transduction* / drug effects
  • Tetrahydronaphthalenes / pharmacology
  • Time Factors


  • Benzoates
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoids
  • Tetrahydronaphthalenes
  • retinoic acid receptor beta
  • Am 580
  • Alcohol Oxidoreductases
  • Hydroxysteroid Dehydrogenases
  • Rdh1 protein, mouse
  • cis-retinol - androgen dehydrogenase