Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury
Induction of Retinol Dehydrogenase 9 Expression in Podocytes Attenuates Kidney Injury
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DOI：
10.1681/asn.2013111150
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发表时间：
2014-09-01
影响因子：
13.6
通讯作者：
He, John Cijiang
中科院分区：
文献类型：
--
作者：
Li, Xuezhu;Dai, Yan;He, John Cijiang
视黄酸的细胞内浓度由将视黄醇转化为视黄酸的两个连续氧化反应决定。我们最近证明，维甲酸的合成显着受损，在肾小球的HIV-1转基因小鼠（Tg 26），HIV相关性肾病的小鼠模型。这种受损的视黄酸合成与视黄醇脱氢酶9的肾表达减少相关，视黄醇脱氢酶9通过将视黄醇转化为视黄醛来催化视黄酸合成的限速步骤。由于维甲酸具有肾脏保护作用，并能诱导足细胞分化，我们假设维甲酸合成的恢复可以减缓肾脏疾病的进展。在此，我们证明了在培养的足细胞中视黄醇脱氢酶9的过度表达诱导足细胞分化标志物的表达。此外，我们证实，足细胞特异性过度表达视黄醇脱氢酶9在小鼠建立肾脏疾病，无论是由于艾滋病毒相关性肾病或阿霉素诱导的肾病减少蛋白尿，减轻肾损伤，并恢复足细胞分化标志物。我们的数据表明，恢复视黄酸的合成可能是一种新的方法来治疗肾脏疾病。
The intracellular concentration of retinoic acid is determined by two sequential oxidation reactions that convert retinol to retinoic acid. We recently demonstrated that retinoic acid synthesis is significantly impaired in glomeruli of HIV-1 transgenic mice (Tg26), a murine model of HIV-associated nephropathy. This impaired retinoic acid synthesis correlates with reduced renal expression of retinol dehydrogenase 9, which catalyzes the rate-limiting step of retinoic acid synthesis by converting retinol to retinal. Because retinoic acid has renal protective effects and can induce podocyte differentiation, we hypothesized that restoration of retinoic acid synthesis could slow the progression of renal disease. Herein, we demonstrate that overexpression of retinol dehydrogenase 9 in cultured podocytes induces the expression of podocyte differentiation markers. Furthermore, we confirm that podocyte-specific overexpression of retinol dehydrogenase 9 in mice with established kidney disease due to either HIV-associated nephropathy or adriamycin-induced nephropathy decreases proteinuria, attenuates kidney injury, and restores podocyte differentiation markers. Our data suggest that restoration of retinoic acid synthesis could be a new approach to treat kidney disease.