Lu Yicheng, Li Heyangzi, Chen Mohan, Lin Yicheng, Zhang Xiaoming
School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
J Transl Med. 2025 Jan 9;23(1):35. doi: 10.1186/s12967-024-06056-z.
The partial epithelial-mesenchymal transition (EMT) is emerging as a significant mechanism in diabetic nephropathy (DN). LOX is a copper amine oxidase conventionally thought to act by crosslinking collagen. However, the role of LOX in partial EMT and fibrotic progression in diabetic nephropathy has not been investigated experimentally.
The bulk RNA sequencing and single-nuclei RNA sequencing (snRNA-seq) analysis were explored to find the role of LOX in diabetic nephropathy. We then investigated the partial EMT and the possible signaling pathway of LOX, both in vivo and in vitro by LOX inhibition experiments in diabetic mice and HK-2 cells. Besides, we further assessed kidney fibrosis and renal function.
LOX expression was elevated in kidneys of diabetic mice. Additionally, snRNA-seq results indicated that LOX expression was higher in partial epithelial-mesenchymal transition proximal tubular (PemtPT) epithelial cells. Moreover, we found that increased LOX prompted partial EMT of renal tubular epithelial cells (RTECs) by modulating the transcription factor Snail both in vivo and in vitro. Remarkably, inhibition of LOX effectively mitigated the partial EMT of RTECs in diabetic mice, thereby attenuating kidney fibrosis and enhancing renal function. Additionally, we identified the TGF-β signaling pathway as an upstream regulator of LOX, and inhibiting LOX partially reversed the partial EMT program in HK-2 cells induced by the TGF-β signaling pathway.
Hyperglycemia induces partial EMT of RTECs via the TGF-β/LOX/Snail axis, thereby contributing to diabetic kidney fibrosis. Inhibiting LOX can effectively reverse the partial EMT of RTECs, diminish diabetic kidney fibrosis, and improve renal function.
部分上皮-间质转化（EMT）正成为糖尿病肾病（DN）的一个重要机制。赖氨氧化酶（LOX）是一种铜胺氧化酶，传统上认为其通过交联胶原蛋白发挥作用。然而，LOX在糖尿病肾病的部分EMT和纤维化进展中的作用尚未进行实验研究。
采用批量RNA测序和单核RNA测序（snRNA-seq）分析来探究LOX在糖尿病肾病中的作用。然后，我们通过对糖尿病小鼠和HK-2细胞进行LOX抑制实验，在体内和体外研究了部分EMT以及LOX可能的信号通路。此外，我们进一步评估了肾纤维化和肾功能。
糖尿病小鼠肾脏中LOX表达升高。此外，snRNA-seq结果表明，部分上皮-间质转化近端肾小管（PemtPT）上皮细胞中LOX表达更高。而且，我们发现体内和体外增加的LOX均通过调节转录因子Snail促使肾小管上皮细胞（RTECs）发生部分EMT。值得注意的是，抑制LOX可有效减轻糖尿病小鼠RTECs的部分EMT，从而减轻肾纤维化并改善肾功能。此外，我们确定TGF-β信号通路是LOX的上游调节因子，抑制LOX可部分逆转由TGF-β信号通路诱导的HK-2细胞中的部分EMT程序。
高血糖通过TGF-β/LOX/Snail轴诱导RTECs发生部分EMT，从而导致糖尿病肾纤维化。抑制LOX可有效逆转RTECs的部分EMT，减少糖尿病肾纤维化并改善肾功能。
