Vitamin D Receptor Signaling in Podocytes Protects against Diabetic Nephropathy
Vitamin D Receptor Signaling in Podocytes Protects against Diabetic Nephropathy
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DOI：
10.1681/asn.2012040383
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发表时间：
2012-12-01
影响因子：
13.6
通讯作者：
Li, Yan Chun
中科院分区：
文献类型：
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作者：
Wang, Youli;Deb, Dilip K.;Li, Yan Chun
维生素D及其类似物具有抗蛋白尿活性，足细胞表达维生素D受体，但足细胞中的维生素D信号传导是否解释了这种肾保护作用尚不清楚。为了研究这个问题，我们使用2.5 kb podocin启动子将Flag标记的人维生素D受体（hVDR）靶向DBA/2 J小鼠的足细胞。在用链脲佐菌素诱导糖尿病后，转基因小鼠的蛋白尿比野生型对照小鼠少。在转基因小鼠中，低剂量的维生素D类似物度骨化醇可预防蛋白尿，显著减弱足细胞丢失和凋亡，并减少肾小球纤维化，但对野生型小鼠糖尿病肾病的进展几乎没有影响。此外，在足细胞中用hVDR转基因重建VDR缺失小鼠，可使VDR缺失小鼠免于严重的糖尿病相关肾损伤。在培养中，1，25-二羟维生素D通过阻断p38和ERK介导的促细胞凋亡途径来抑制高糖诱导的足细胞凋亡。总之，这些数据提供了强有力的证据，足细胞中的维生素D/VDR信号传导在保护肾脏免受糖尿病损伤中起着关键作用。
Vitamin D and its analogs have antiproteinuric activity and podocytes express the vitamin D receptor, but whether vitamin D signaling in podocytes accounts for this renoprotection is unknown. To investigate this question, we used the 2.5 kb podocin promoter to target Flag-tagged human vitamin D receptor (hVDR) to podocytes in DBA/2J mice. After the induction of diabetes with streptozotocin, transgenic mice had less albuminuria than wild-type controls. In transgenic mice, a low dose of the vitamin D analog doxercalciferol prevented albuminuria, markedly attenuated podocyte loss and apoptosis, and reduced glomerular fibrosis, but it had little effect on the progression of diabetic nephropathy in wild-type mice. Moreover, reconstitution of VDR-null mice with the hVDR transgene in podocytes rescued VDR-null mice from severe diabetes-related renal damage. In culture, 1,25-dihydroxyvitamin D suppressed high-glucose-induced apoptosis of podocytes by blocking p38- and ERK-mediated proapoptotic pathways. Taken together, these data provide strong evidence that vitamin D/VDR signaling in podocytes plays a critical role in the protection of the kidney from diabetic injury.