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Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.

Abstract
Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phosphodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection.
AuthorsYifei Zhong, Yingwei Wu, Ruijie Liu, Yueyi Deng, Sandeep K Mallipattu, Paul E Klotman, Peter Y Chuang, John C He
JournalKidney international (Kidney Int) Vol. 81 Issue 9 Pg. 856-64 (May 2012) ISSN: 1523-1755 [Electronic] United States
PMID22258322 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Aminopyridines
  • Benzamides
  • Benzoates
  • Cyclopropanes
  • Phosphodiesterase 4 Inhibitors
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Tetrahydronaphthalenes
  • Roflumilast
  • Am 580
  • Cyclic AMP
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Cyclic AMP-Dependent Protein Kinases
Topics
  • AIDS-Associated Nephropathy (genetics, metabolism, pathology, prevention & control, virology)
  • Aminopyridines (pharmacology)
  • Animals
  • Benzamides (pharmacology)
  • Benzoates (pharmacology)
  • CREB-Binding Protein (metabolism)
  • Cell Differentiation (drug effects)
  • Cyclic AMP (metabolism)
  • Cyclic AMP-Dependent Protein Kinases (metabolism)
  • Cyclopropanes (pharmacology)
  • Cytoprotection
  • Disease Models, Animal
  • Disease Progression
  • Drug Therapy, Combination
  • Female
  • HIV Infections (complications, drug therapy, genetics, virology)
  • HIV-1 (genetics, pathogenicity)
  • Kidney Tubules (drug effects, metabolism, pathology, virology)
  • Male
  • Mice
  • Mice, Transgenic
  • Phosphodiesterase 4 Inhibitors (pharmacology)
  • Phosphorylation
  • Proteinuria (prevention & control, virology)
  • Receptors, Retinoic Acid (agonists, metabolism)
  • Renal Insufficiency (genetics, metabolism, pathology, prevention & control, virology)
  • Retinoic Acid Receptor alpha
  • Signal Transduction (drug effects)
  • Tetrahydronaphthalenes (pharmacology)
  • Time Factors

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