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Abstract：
Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a unique component of the ubiquitin-proteasome system (UPS), which has multiple activities in maintaining intracellular ubiquitin levels. We previously reported the aberrant low expression of UCHL1 in podocytes of non-immune complex-mediated glomerulonephritis, and recent studies indicate that anti-UCHL1 antibody was responsible for the refractory minimal change disease (MCD), but the specific effect of UCHL1 to the podocytopathy has not been determined. Therefore, we generated podocyte-specific UCHL1 gene knockout (UCHL1cre/cre) rats model. Podocyte-specific UCHL1 knockout rats exhibited severe kidney damage, including segmental/global glomerulosclerosis, kidney function damage and severe proteinuria, compared with littermate control. Subsequently, by carrying out mass spectrometry analysis of isolated glomeruli of rats, abnormal protein accumulation of ECM-receptor Interaction was found in UCHL1cre/cre rats. Mechanistic studies in vivo and in vitro revealed that aberrant protein accumulation after UCHL1 deficiency induced endoplasmic reticulum (ER) stress, unfolded protein reaction (UPR) to reduce the protein level of podocyte skeleton proteins, and CHOP mediated apoptosis as well, which related to the dysfunction of the ubiquitin-proteasome system with decreased free monomeric ubiquitin level, thereby affecting protein ubiquitination and degradation. In addition, inhibition of ER stress by 4-PBA could attenuate the degree of ER stress and podocyte dysfunction. Our study indicates that UCHL1 is a potential target for preventing podocytes injury in some non-immune complex-mediated glomerulopathy.
摘要：
泛素羧基末端水解酶L1（UCHL1）是泛素-蛋白酶体系统（UPS）的独特组成部分，具有维持细胞内泛素水平的多种活性。我们先前报道了UCHL1在非免疫复合物介导的肾小球肾炎足细胞中的异常低表达，和最近的研究表明，抗UCHL1抗体负责难治性微小病变疾病（MCD），但UCHL1对足细胞病的具体作用尚未确定。因此,我们建立了足细胞特异性UCHL1基因敲除（UCHL1cre/cre）大鼠模型。足细胞特异性UCHL1基因敲除大鼠表现出严重的肾脏损伤，包括节段性/全球性肾小球硬化，肾功能损害和严重的蛋白尿，与同窝对照相比。随后，通过对分离的大鼠肾小球进行质谱分析，在UCHL1cre/cre大鼠中发现ECM-受体相互作用的异常蛋白积累。体内和体外的机制研究表明，UCHL1缺乏后异常的蛋白质积累诱导内质网（ER）应激，解折叠蛋白反应（UPR）降低足细胞骨架蛋白的蛋白水平，和CHOP介导的细胞凋亡，这与泛素-蛋白酶体系统的功能障碍有关，游离单体泛素水平降低，从而影响蛋白质的泛素化和降解。此外,4-PBA抑制内质网应激可以减轻内质网应激和足细胞功能障碍的程度。我们的研究表明，在一些非免疫复合物介导的肾小球病中，UCHL1是预防足细胞损伤的潜在靶标。
