Department of Internal Medicine, Division of Endocrinology and Metabolism, Gunma University Graduate School of Medicine, 3-39-15, Showa, Maebashi 371-8511, Japan.
Division of Biomedical Sciences, Warwick Medical School, Coventry CV4 7AL, UK.
Cells. 2023 Apr 20;12(8):1197. doi: 10.3390/cells12081197.
Autophagy is involved in the development of diabetic kidney disease (DKD), the leading cause of end-stage renal disease. The Fyn tyrosine kinase (Fyn) suppresses autophagy in the muscle. However, its role in kidney autophagic processes is unclear. Here, we examined the role of Fyn kinase in autophagy in proximal renal tubules both in vivo and in vitro. Phospho-proteomic analysis revealed that transglutaminase 2 (Tgm2), a protein involved in the degradation of p53 in the autophagosome, is phosphorylated on tyrosine 369 (Y369) by Fyn. Interestingly, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy in proximal renal tubules in vitro, and that p53 expression is decreased upon autophagy in Tgm2-knockdown proximal renal tubule cell models. Using streptozocin (STZ)-induced hyperglycemic mice, we confirmed that Fyn regulated autophagy and mediated p53 expression via Tgm2. Taken together, these data provide a molecular basis for the role of the Fyn-Tgm2-p53 axis in the development of DKD.
自噬参与糖尿病肾病（DKD）的发生发展，DKD 是终末期肾病的主要病因。原癌基因 Fyn 酪氨酸激酶（Fyn）可抑制肌肉中的自噬。然而，其在肾脏自噬过程中的作用尚不清楚。本研究在体、体外水平，探讨了 Fyn 激酶在近端肾小管自噬中的作用。磷酸化蛋白质组学分析表明，转谷氨酰胺酶 2（Tgm2）是自噬体中 p53 降解途径的关键蛋白，其酪氨酸 369（Y369）可被 Fyn 磷酸化。有趣的是，我们发现 Fyn 依赖性 Tgm2 磷酸化调节体外近端肾小管自噬，且在 Tgm2 敲低的近端肾小管细胞模型中，自噬时 p53 表达降低。使用链脲佐菌素（STZ）诱导的高血糖小鼠模型，我们证实 Fyn 通过 Tgm2 调节自噬并介导 p53 表达。综上，这些数据为 Fyn-Tgm2-p53 轴在 DKD 发生发展中的作用提供了分子基础。
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