Fan Zhibin, Zhang Yue, Yuan Liming, Gao Yuan, Tian Xiaoxi, Tian Jin, Wan Jie, Li Bingyu, Wang Xiaoqi, Wang Shuo, Zhang Lianshan, Wang Lei, Zhou Pengxiang, Liu Wei
Department of Pathology and Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang 050017, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, Hebei, China; Department of Proctology, Tangshan Gongren Hospital, Tangshan 063000, China.
Department of Clinical Diagnostics, Hebei Medical University, Shijiazhuang 050017, China.
Cell Signal. 2025 Oct;134:111955. doi: 10.1016/j.cellsig.2025.111955. Epub 2025 Jun 20.
Diabetic kidney disease (DKD) progression is predominantly attributed to podocyte injury. However, the underlying mechanisms remain inadequately understood. DKD patients exhibit elevated lactate concentrations due to impaired glucose metabolism. Lactate serves as a substrate for a post-translational modification known as lactylation, which is integral to numerous cellular processes. The study aimed to explore the potential role of lactylation in DKD podocyte injury and to elucidate its underlying mechanisms. The results showed that lactate concentrations were elevated in the plasma of DKD patients, as well as in the serum and renal tissue of diabetic mice. High glucose (HG) resulted in increased lactate accumulation in podocytes, exacerbated podocyte injury and promoted protein lactylation. Protein modification omics demonstrated that LARS1 lactylation was enhanced, specifically at the K970 site, which further aggravated podocyte injury by inhibiting autophagy and promoting apoptosis. In vivo transfection with LARS1 siRNA significantly improved renal function and mitigated podocyte injury. Our study identified a novel mechanism linking LARS1 lactylation activity to compromised podocyte autophagy, heightened podocyte injury, and the onset of proteinuria within DKD.
糖尿病肾病（DKD）的进展主要归因于足细胞损伤。然而，其潜在机制仍未得到充分了解。由于葡萄糖代谢受损，DKD患者的乳酸浓度升高。乳酸作为一种翻译后修饰（称为乳酰化）的底物，这一修饰对于众多细胞过程至关重要。该研究旨在探讨乳酰化在DKD足细胞损伤中的潜在作用，并阐明其潜在机制。结果显示，DKD患者血浆以及糖尿病小鼠血清和肾组织中的乳酸浓度均升高。高糖（HG）导致足细胞中乳酸积累增加，加剧足细胞损伤并促进蛋白质乳酰化。蛋白质修饰组学表明，LARS1的乳酰化增强，特别是在K970位点，这通过抑制自噬和促进凋亡进一步加重足细胞损伤。体内转染LARS1 siRNA可显著改善肾功能并减轻足细胞损伤。我们的研究确定了一种新机制，将LARS1乳酰化活性与DKD中足细胞自噬受损、足细胞损伤加剧和蛋白尿的发生联系起来。
