Podocyte injury leads to impaired filtration barrier function of the kidney that underlies the pathophysiology of idiopathic nephrotic syndrome (INS), the most common NS occurring in children. The heat shock protein 90 (Hsp90) is involved in the regulation of apoptosis in a variety of cell types, however, little is known about its role in podocytes and whether it associated with NS. Here, we show that Hsp90 is upregulated in glomeruli podocytes from mice with adriamycin (ADR)-induced nephropathy, and that it is also upregulated in an immortalized podocyte cell line treated with ADR in vitro, together suggesting an association of Hsp90 upregulation in podocytes with NS pathogenesis. Functionally, Hsp90 inhibition with PU-H71 aggravates ADR-induced podocyte apoptosis and worsens the impairment of filtration barrier function. Mechanistically, Hsp90 inhibition with PU-H71 enhances the activation of intrinsic apoptotic pathway, and moreover, blockade of podocyte apoptosis with zVAD-fmk (aVAD), a pan-caspase inhibitor, abrogates effects of Hsp90 inhibition on filtration barrier function of ADR-treated podocytes, thus demonstrating that Hsp90 inhibition aggravates ADR-induced podocyte injury through intrinsic apoptosis pathway. In sum, this study reveals a detrimental role of Hsp90 inhibition in podocyte injury, which may offer it as a potential therapeutic target in NS therapy.

中文翻译：

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Hsp90抑制通过内在的凋亡途径加重阿霉素诱导的足细胞损伤。

足细胞损伤导致肾脏的滤过屏障功能受损，这是特发性肾病综合征（INS）的病理生理基础，这是儿童中最常见的NS。热休克蛋白90（Hsp90）参与多种细胞类型的凋亡调控，但是，关于其在足细胞中的作用以及是否与NS相关的了解甚少。在这里，我们显示Hsp90在阿霉素（ADR）诱导的肾病小鼠肾小球足细胞中被上调，并且在用ADR体外治疗的永生化足细胞中也被上调，共同表明足细胞中Hsp90上调与NS发病机理。在功能上，用PU-H71抑制Hsp90会加重ADR诱导的足细胞凋亡，并使过滤屏障功能受损。机械上，用PU-H71抑制Hsp90可增强内在凋亡途径的激活，此外，用泛半胱天冬酶抑制剂zVAD-fmk（aVAD）阻断足细胞凋亡，可消除Hsp90抑制作用对ADR处理的足细胞的过滤屏障功能的影响，因此证明Hsp90抑制通过内在的细胞凋亡途径加重了ADR诱导的足细胞损伤。总之，这项研究揭示了Hsp90抑制在足细胞损伤中的有害作用，这可能使其成为NS治疗中的潜在治疗靶标。因此证明Hsp90抑制通过内在的细胞凋亡途径加重了ADR诱导的足细胞损伤。总之，这项研究揭示了Hsp90抑制在足细胞损伤中的有害作用，这可能使其成为NS治疗中的潜在治疗靶标。因此证明Hsp90抑制通过内在的细胞凋亡途径加重了ADR诱导的足细胞损伤。总而言之，这项研究揭示了Hsp90抑制在足细胞损伤中的有害作用，这可能使其成为NS治疗中的潜在治疗靶标。