Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, USA; Division of Nephrology, Zhongshan Hospital, Xiamen University, Xiamen, China.
Kidney Int. 2017 Dec;92(6):1444-1457. doi: 10.1016/j.kint.2017.04.026. Epub 2017 Jul 27.
Proliferation of glomerular epithelial cells, including podocytes, is a key histologic feature of crescentic glomerulonephritis. We previously found that retinoic acid (RA) inhibits proliferation and induces differentiation of podocytes by activating RA receptor-α (RARα) in a murine model of HIV-associated nephropathy. Here, we examined whether RA would similarly protect podocytes against nephrotoxic serum-induced crescentic glomerulonephritis and whether this effect was mediated by podocyte RARα. RA treatment markedly improved renal function and reduced the number of crescentic lesions in nephritic wild-type mice, while this protection was largely lost in mice with podocyte-specific ablation of Rara (Pod-Rara knockout). At a cellular level, RA significantly restored the expression of podocyte differentiation markers in nephritic wild-type mice, but not in nephritic Pod-Rara knockout mice. Furthermore, RA suppressed the expression of cell injury, proliferation, and parietal epithelial cell markers in nephritic wild-type mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to the coexpression of podocyte and parietal epithelial cell markers in a small subset of glomerular cells in nephritic mice, suggesting that RA may induce transdifferentiation of parietal epithelial cells toward a podocyte phenotype. In vitro, RA directly inhibited the proliferation of parietal epithelial cells and enhanced the expression of podocyte markers. In vivo lineage tracing of labeled parietal epithelial cells confirmed that RA increased the number of parietal epithelial cells expressing podocyte markers in nephritic glomeruli. Thus, RA attenuates crescentic glomerulonephritis primarily through RARα-mediated protection of podocytes and in part through the inhibition of parietal epithelial cell proliferation and induction of their transdifferentiation into podocytes.
肾小球上皮细胞（包括足细胞）的增殖是新月体性肾小球肾炎的主要组织学特征。我们之前发现，视黄酸（RA）通过激活 HIV 相关肾病模型中的视黄酸受体-α（RARα），抑制足细胞增殖并诱导其分化。在这里，我们研究了 RA 是否同样可以保护足细胞免受肾毒性血清诱导的新月体性肾小球肾炎的影响，以及这种作用是否通过足细胞 RARα介导。RA 治疗显著改善了肾功能并减少了肾炎野生型小鼠的新月体病变数量，而在足细胞特异性 Rara 缺失（Pod-Rara 敲除）的小鼠中，这种保护作用则大大丧失。在细胞水平上，RA 显著恢复了肾炎野生型小鼠中足细胞分化标志物的表达，但在肾炎 Pod-Rara 敲除小鼠中则没有。此外，RA 抑制了肾炎野生型小鼠中细胞损伤、增殖和壁细胞标志物的表达，而在肾炎 Pod-Rara 敲除小鼠中，这些标志物的表达均显著减弱。有趣的是，RA 治疗导致肾炎小鼠的一小部分肾小球细胞中同时表达足细胞和壁细胞标志物，这表明 RA 可能诱导壁细胞向足细胞表型的转分化。在体外，RA 直接抑制壁细胞的增殖并增强足细胞标志物的表达。体内标记壁细胞的谱系追踪证实，RA 增加了肾炎肾小球中表达足细胞标志物的壁细胞数量。因此，RA 主要通过 RARα 介导的足细胞保护作用，部分通过抑制壁细胞增殖和诱导其向足细胞转分化来减轻新月体性肾小球肾炎。
