Journal
KIDNEY INTERNATIONAL
Volume 81, Issue 9, Pages 856-864Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ki.2011.467
Keywords
collapsing glomerulopathy; glomerular disease; HIV nephropathy; podocyte; signaling
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Funding
- NIH [1R01DK078897, 1R01DK088541, P01-DK-56492, 5K08DK082760]
- VA Merit Award
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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-alpha (RAR alpha)/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 RAR alpha 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 RAR alpha agonists to provide additional renal protection. Kidney International (2012) 81, 856-864; doi:10.1038/ki.2011.467; published online 18 January 2012
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