State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Division of Nephrology, The First People's Hospital of Foshan, Foshan, China.
Division of Nephrology, The First People's Hospital of Foshan, Foshan, China.
Free Radic Biol Med. 2023 Nov 20;209(Pt 1):40-54. doi: 10.1016/j.freeradbiomed.2023.09.039. Epub 2023 Oct 2.
Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.
足细胞损伤是肾小球疾病的标志之一，也是慢性肾脏病（CKD）的主要原因之一。过氧化物酶体增殖物激活受体α（PPARα）在足细胞脂肪酸氧化（FAO）中起关键作用。然而，其潜在的调节机制仍未解决。Trim63 是一种 E3 泛素连接酶，已被证明能抑制 PPARα 的活性；然而，其在肾脏中脂肪酸代谢中的作用迄今尚未阐明。在这项研究中，我们研究了在阿霉素（ADR）诱导的肾病和糖尿病肾病模型以及足细胞系中转录因子 Trim63 过表达和敲低的影响。在蛋白尿性 CKD 的啮齿动物和人类患者中，Trim63 上调，特别是在损伤肾小球的足细胞中。在 ADR 诱导的肾病模型中，异位 Trim63 的应用加重了 FAO 缺陷和线粒体功能障碍，并引发强烈的脂质沉积、足细胞损伤和蛋白尿。值得注意的是，Trim63 抑制减轻了 FAO 缺陷和线粒体功能障碍，并显著恢复了 ADR 诱导和糖尿病肾病（DN）模型中的足细胞损伤和肾纤维化。此外，观察到 Trim63 介导 PPARα 的泛素化和降解，导致足细胞损伤。我们证明了 Trim63 在肾脏组织中的病理作用，以前未被认识到，在 FAO 缺陷和足细胞损伤中起作用。靶向 Trim63 可能是治疗足细胞损伤和蛋白尿的一种可行策略。
