Retinoic acid improves nephrotoxic serum-induced glomerulonephritis through activation of podocyte retinoic acid receptor α.
Retinoic acid improves nephrotoxic serum-induced glomerulonephritis through activation of podocyte retinoic acid receptor α.
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DOI：
10.1016/j.kint.2017.04.026
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发表时间：
2017-12
影响因子：
19.6
通讯作者：
He JC
中科院分区：
文献类型：
--
作者：
Dai Y;Chen A;Liu R;Gu L;Sharma S;Cai W;Salem F;Salant DJ;Pippin JW;Shankland SJ;Moeller MJ;Ghyselinck NB;Ding X;Chuang PY;Lee K;He JC
肾小球上皮细胞，包括足细胞的增殖是新月体肾小球肾炎的一个重要组织学特征。我们以前发现，维甲酸（RA）通过激活RA受体-α（RARα）在HIV相关肾病小鼠模型中抑制足细胞增殖并诱导足细胞分化。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肾小球肾炎，以及这种作用是否由足细胞RARα介导。RA治疗显着改善肾功能，并减少了肾炎野生型小鼠的新月体病变的数量，而这种保护在Rara的足细胞特异性消融（Pod-Rara敲除）的小鼠中基本丧失。在细胞水平，RA显着恢复足细胞分化标志物的表达在肾炎野生型小鼠，但不是在肾炎Pod-Rara基因敲除小鼠。此外，RA抑制了肾炎野生型小鼠中细胞损伤、增殖和壁上皮细胞标志物的表达，所有这些在肾炎Pod-Rara敲除小鼠中均显著减弱。有趣的是，RA治疗导致共表达足细胞和壁上皮细胞标志物在一个小的肾小球细胞在肾炎小鼠的子集，表明RA可能会诱导壁上皮细胞转分化向足细胞表型。在体外，RA直接抑制壁上皮细胞的增殖，并增强足细胞标志物的表达。在体内标记壁上皮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记物的壁上皮细胞的数量。因此，RA主要通过RARα介导的足细胞保护以及部分通过抑制壁上皮细胞增殖和诱导其转分化为足细胞来减轻新月体肾小球肾炎。
Proliferation of glomerular epithelial cells, including the 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 wildtype 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 wildtype 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 wildtype mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to 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 towards 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.
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DOI：
10.1097/01.asn.0000102468.37809.c6
发表时间：
2004-01-01
影响因子：
13.6
作者：
Moeller, MJ;Soofi, A;Holzman, LB
通讯作者：
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DOI：
10.1152/ajprenal.00026.2001
发表时间：
2002-04-01
影响因子：
4.2
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影响因子：
13.6
作者：
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通讯作者：
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影响因子：
3.9
作者：
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通讯作者：
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影响因子：
25
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