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Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway

John Cijiang He1, Ting-Chi Lu, Margaret Fleet

  • 1Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. cijiang.he@mssm.edu

Journal of the American Society of Nephrology : JASN
|December 22, 2006
PubMed

Insights

All-trans retinoic acid (atRA) reverses HIV-1 podocyte damage by increasing cAMP levels, restoring differentiation markers and inhibiting proliferation. This treatment also reduced proteinuria and glomerulosclerosis in HIV-1-transgenic mice.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Virology

Background:

  • HIV-associated nephropathy involves renal podocyte proliferation and dedifferentiation.
  • Understanding the molecular mechanisms underlying podocyte dysfunction in HIV-1 infection is crucial.

Purpose of the Study:

  • To investigate the therapeutic potential of all-trans retinoic acid (atRA) in reversing HIV-1-induced podocyte abnormalities.
  • To elucidate the intracellular signaling pathways, particularly cAMP-mediated pathways, involved in atRA's effects on HIV-1-infected podocytes.

Main Methods:

  • Treatment of HIV-1-infected podocytes with atRA and other retinoids.
  • Assessment of cell proliferation, differentiation markers (synaptopodin, nephrin, podocin, WT-1), and intracellular cAMP levels.
  • Pharmacological manipulation using receptor antagonists (RARalpha antagonists), cAMP analogs (forskolin, 8-bromo-cAMP), and pathway inhibitors (Rp-cAMP, rolipram).
  • In vivo studies using HIV-1-transgenic mice to evaluate proteinuria, cell proliferation, and glomerulosclerosis.

Main Results:

  • atRA treatment reduced proliferation and restored differentiation markers in HIV-1-infected podocytes.
  • atRA and 9-cis RA increased intracellular cAMP levels; this effect was RARalpha-dependent.
  • Exogenous cAMP stimulation mimicked atRA's antiproliferative and differentiation-restoring effects.
  • atRA's effects were dependent on the cAMP/protein kinase A pathway and involved suppression of MAPK and Stat3 phosphorylation.
  • In vivo, atRA ameliorated proteinuria, proliferation, and glomerulosclerosis in HIV-1-transgenic mice.

Conclusions:

  • atRA effectively reverses the detrimental effects of HIV-1 on podocytes through a mechanism involving RARalpha-mediated cAMP production.
  • The findings highlight the therapeutic potential of atRA for managing HIV-associated nephropathy.
  • Targeting the cAMP pathway offers a promising strategy for treating HIV-1-induced kidney disease.

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