ntracellular domain. Background Tubular senescence is a major determinant of CKD, and identification of potential therapeutic targets involved in senescent tubular epithelial cells has clinical importance. Lysosomal-associated protein transmembrane 5 (LAPTM5) is a key molecule related to T- and B-cell receptor expression and inflammation. However, the expression pattern of LAPTM5 in the kidney and the contribution of LAPTM5 to the development of CKD are unknown. Methods Laptm5−/− mice and tubule specific–Laptm5 knockout mice were used to examine the role of LAPTM5 in tubular senescence by establishing different experimental mouse CKD models. Results LAPTM5 expression was significantly induced in the kidney, especially in proximal tubules and distal convoluted tubules, from mice with aristolochic acid nephropathy, bilateral ischemia/reperfusion injury–induced CKD, or unilateral ureter obstruction. Tubule-specific deletion of Laptm5 inhibited senescence of tubular epithelial cells and alleviated tubulointerstitial fibrosis in aged mice. Moreover, Laptm5 deficiency ameliorated kidney injury and tubular senescence in mice with CKD. Mechanistically, LAPTM5 inhibited ubiquitination of notch1 intracellular domain by mediating WWP2 lysosomal degradation and then leading to cellular senescence in tubular epithelial cells. We also observed a higher expression of LAPTM5 in tubules from patients with CKD, and the level of LAPTM5 was correlated with kidney fibrosis and tubular senescence in people with CKD. Conclusions LAPTM5 contributed to tubular senescence by regulating the WWP2/notch1 intracellular domain signaling pathway and exacerbated kidney injury during the progression of CKD....

中文翻译：

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溶酶体相关蛋白跨膜 5、肾小管衰老和 CKD 进展


ntracellular 结构域。背景 肾小管衰老是 CKD 的主要决定因素，确定参与衰老肾小管上皮细胞的潜在治疗靶点具有临床意义。溶酶体相关蛋白跨膜 5 （LAPTM5） 是与 T 细胞和 B 细胞受体表达和炎症相关的关键分子。然而，LAPTM5 在肾脏中的表达模式以及 LAPTM5 对 CKD 发展的贡献尚不清楚。方法 使用Laptm5 −/−小鼠和肾小管特异性-Laptm5 敲除小鼠，通过建立不同的实验小鼠 CKD 模型来检验 LAPTM5 在肾小管衰老中的作用。结果 马兜铃酸肾病、双侧缺血/再灌注损伤诱导的 CKD 或单侧输尿管梗阻小鼠的肾脏中显著诱导 LAPTM5 表达，尤其是在近端小管和远端曲小管中。Laptm5 的小管特异性缺失抑制了小管上皮细胞的衰老，并减轻了老年小鼠的肾小管间质纤维化。此外，Laptm5 缺陷改善了 CKD 小鼠的肾损伤和肾小管衰老。从机制上讲，LAPTM5 通过介导 WWP2 溶酶体降解抑制 Notch1 细胞内结构域的泛素化，然后导致肾小管上皮细胞的细胞衰老。我们还观察到 CKD 患者小管中 LAPTM5 的表达较高，LAPTM5 水平与 CKD 患者的肾纤维化和肾小管衰老相关。结论 LAPTM5 通过调节 WWP2/Notch1 胞内结构域信号通路促进肾小管衰老，并在 CKD 进展过程中加剧肾损伤。