R168H and V165X mutant podocin might induce different degrees of podocyte injury via different molecular mechanisms
R168H and V165X mutant podocin might induce different degrees of podocyte injury via different molecular mechanisms
复制标题
R168H和V165X突变体podocin可能通过不同的分子机制诱导不同程度的足细胞损伤
DOI：
10.1111/j.1365-2443.2009.01336.x
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发表时间：
2009-09-01
期刊：
影响因子：
2.1
通讯作者：
Guan, Na
中科院分区：
文献类型：
--
作者：
Fan, Qingfeng;Zhang, Han;Guan, Na
足细胞裂隙隔(SD)的关键蛋白podocin在遗传性和散发性局灶性节段性肾小球硬化(FSGS)中均有大量突变。然而，突变的足菌素诱导足细胞损伤的机制仍不清楚。在我们的FSGS患者中发现了一个复合杂合子Podocin突变，导致截短(Podocin V165X)和错义突变蛋白(Podocin R168H)。在这里，我们探讨了这两种突变的足细胞因子是否以及如何在体外培养的足细胞系中诱导足细胞损伤。我们的结果表明，与Podocin V165X相比，Podocin R168H诱导了更多的足细胞凋亡和更多的足细胞分子的表达变化。TRPC6基因敲除可有效抑制正常定位的Podocin V165X引起的足细胞损伤。Podocin R168H在内质网(ER)的异常滞留导致了其他关键SD分子newitin、CD2AP和TRPC6的错误定位，并显著上调了ER应激标记Bip/GRP78、p-perk和caspase-12。这些结果表明，R168H和V165X对足细胞的损伤程度不同，这可能是不同的分子机制所致。我们的发现为进一步探索不同突变的Podocin诱导的蛋白尿的药理靶点提供了一些可能的线索。
A lot of mutations of podocin, a key protein of podocyte slit diaphragm (SD), have been found both in hereditary and sporadic focal segmental glomeruloscleorosis (FSGS). Nevertheless, the mechanisms of podocyte injury induced by mutant podocins are still unclear. A compound heterozygous podocin mutation was identified in our FSGS patient, leading to a truncated (podocin V165X) and a missense mutant protein (podocin R168H), respectively. Here, it was explored whether and how both mutant podocins induce podocyte injury in the in vitro cultured podocyte cell line. Our results showed that podocin R168H induced more significant podocyte apoptosis and expression changes in more podocyte molecules than podocin V165X. Podocyte injury caused by the normal localized podocin V165X was effectively inhibited by TRPC6 knockdown. The abnormal retention of podocin R168H in endoplasmic reticulum ( ER) resulted in the mis-localizations of other critical SD molecules nephrin, CD2AP and TRPC6, and significantly up-regulated ER stress markers Bip/grp78, p-PERK and caspase-12. These results implicated that podocin R168H and podocin V165X induced different degrees of podocyte injury, which might be resulted from different molecular mechanisms. Our findings provided some possible clues for further exploring the pharmacological targets to the proteinuria induced by different mutant podocins.