Department of Paediatrics, The First Affiliated Hospital of Henan University of Science & Technology, Luoyang, Henan, 471000, China.
Department of Paediatrics, The First Affiliated Hospital of Henan University of Science & Technology, Luoyang, Henan, 471000, China.
Exp Cell Res. 2020 May 15;390(2):111928. doi: 10.1016/j.yexcr.2020.111928. Epub 2020 Mar 7.
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.
足细胞损伤导致肾脏滤过屏障功能受损，这是特发性肾病综合征（INS）的病理生理学基础，INS 是儿童最常见的肾病。热休克蛋白 90（Hsp90）参与多种细胞类型的细胞凋亡调节，然而，其在足细胞中的作用及其与 NS 的关系知之甚少。在这里，我们表明，阿霉素（ADR）诱导的肾病小鼠肾小球足细胞中 Hsp90 上调，体外用 ADR 处理的永生化足细胞系中也上调，这表明 Hsp90 在足细胞中的上调与 NS 的发病机制有关。功能上，用 PU-H71 抑制 Hsp90 会加重 ADR 诱导的足细胞凋亡，并使滤过屏障功能受损加重。在机制上，用 PU-H71 抑制 Hsp90 会增强内在凋亡途径的激活，此外，用广谱半胱天冬酶抑制剂 zVAD-fmk（aVAD）阻断足细胞凋亡，会消除 Hsp90 抑制对 ADR 处理的足细胞滤过屏障功能的影响，从而表明 Hsp90 抑制通过内在凋亡途径加重 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，这可能为 NS 治疗提供一个潜在的治疗靶点。
