Impairment of Proteasome Function in Podocytes Leads to CKD
Impairment of Proteasome Function in Podocytes Leads to CKD
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DOI：
10.1681/asn.2019101025
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发表时间：
2021-03-01
影响因子：
13.6
通讯作者：
Asanuma, Katsuhiko
中科院分区：
文献类型：
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作者：
Makino, Shin-ichi;Shirata, Naritoshi;Asanuma, Katsuhiko
背景泛素-蛋白酶体系统(UPS)和自噬-溶酶体系统(APLS)是细胞内主要的降解过程。APLS在足细胞中的重要性已得到证实，但UPS在足细胞中的作用尚未被很好地了解。方法建立Rpt3(PdKO)缺失小鼠，Rpt3(PdKO)编码构建26S蛋白酶体及其去泛素功能所必需的调节亚基。结果Rpt3(PdKO)小鼠出现蛋白尿和肾小球硬化，导致CKD。蛋白酶体功能受损导致泛素化蛋白和氧化修饰蛋白的积聚，并诱导足细胞凋亡。虽然蛋白酶体功能受损通常会诱导自噬活性，但Rpt3(PdKO)小鼠足细胞的自噬小体数量低于对照组，这表明蛋白酶体功能受损的足细胞自噬活性受到抑制。在体外研究中，抗氧化剂apocynin和自噬激活剂雷帕霉素抑制蛋白酶体抑制诱导的足细胞凋亡。此外，雷帕霉素还能改善Rpt3(PdKO)小鼠的肾小球损伤。在Rpt3(PdKO)小鼠的足细胞中检测到泛素化蛋白和氧化修饰蛋白的积累是衰老的一个特征。Rpt3(PdKO)小鼠足细胞衰老标志物增加，提示蛋白酶体功能受损促进足细胞衰老。结论足细胞蛋白酶体功能受损导致CKD，抗氧化剂和自噬激活剂可作为年龄依赖性CKD的治疗药物。
Background The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood.Methods To investigate the role of the UPS in podocytes, mice were generated that had deletion of Rpt3 (Rpt3(pdKO)) which encodes an essential regulatory subunit required for construction of the 26S proteasome and its deubiquitinating function.Results Rpt3(PdKO) mice showed albuminuria and glomerulosclerosis, leading to CKD. Impairment of proteasome function caused accumulation of ubiquitinated proteins and of oxidative modified proteins, and it induced podocyte apoptosis. Although impairment of proteasome function normally induces autophagic activity, the number of autophagosomes was lower in podocytes of Rpt3(PdKO) mice than in control mice, suggesting the autophagic activity was suppressed in podocytes with impairment of proteasome function. In an in vitro study, antioxidant apocynin and autophagy activator rapamycin suppressed podocyte apoptosis induced by proteasome inhibition. Moreover, rapamycin ameliorated the glomerular injury in the Rpt3(PdKO) mice. The accumulation of ubiquitinated proteins and of oxidative modified proteins, which were detected in the podocytes of Rpt3(PdKO) mice, is a characteristic feature of aging. An aging marker was increased in the podocytes of Rpt3(PdKO) mice, suggesting that impairment of proteasome function promoted signs of aging in podocytes.Conclusions Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.