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.
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Authors | Yifei Zhong, Yingwei Wu, Ruijie Liu, Yueyi Deng, Sandeep K Mallipattu, Paul E Klotman, Peter Y Chuang, John C He |
Journal | Kidney international
(Kidney Int)
Vol. 81
Issue 9
Pg. 856-64
(May 2012)
ISSN: 1523-1755 [Electronic] United States |
PMID | 22258322
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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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
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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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