Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Kidney Int. 2012 May;81(9):856-64. doi: 10.1038/ki.2011.467. Epub 2012 Jan 18.
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.
维甲酸通过保护足细胞免受损伤，可减少几种肾脏病动物模型的蛋白尿和肾小球硬化。我们最近的体外研究表明，全反式维甲酸通过激活维甲酸受体-α（RARα）/cAMP/PKA/CREB 通路诱导足细胞分化。当与全反式维甲酸联合使用时，磷酸二酯酶 4 的抑制剂通过增加细胞内 cAMP 进一步增强足细胞分化。此外，我们发现，特异性 RARα 激动剂 Am580 在一种模仿人类 HIV 相关肾病的 HIV-1 转基因小鼠衍生的快速进行性肾功能衰竭（HIV-Tg）克隆中具有与全反式维甲酸相似的肾脏保护作用。用磷酸二酯酶 4 抑制剂罗氟司特或 Am580 治疗可显著减少蛋白尿、减轻肾脏损伤，并改善这些 HIV-Tg 小鼠的足细胞分化。当罗氟司特与 Am580 联合使用时，还发现了其他肾脏保护作用。与体外数据一致，用 Am580 和罗氟司特治疗的 HIV-Tg 小鼠的肾小球中磷酸化 CREB 的活性高于单独使用任一药物。因此，磷酸二酯酶 4 抑制剂可与 RARα 激动剂联合使用，以提供额外的肾脏保护。
