Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, NY, United States.
Sci Rep. 2017 Mar 23;7(1):323. doi: 10.1038/s41598-017-00305-6.
We previously reported a critical role of reticulon (RTN) 1A in mediating endoplasmic reticulum (ER) stress in kidney tubular cells and the expression of RTN1A correlates with the renal function and the severity of kidney injury in patients with diabetic nephropathy (DN). Here, we determined the roles of RTN1A and ER stress in podocyte injury and DN. We used db/db mice with early unilateral nephrectomy (Unx) as a murine model of progressive DN and treated mice with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress. We found increased expression of RTN1A and ER stress markers in the kidney of db/db-Unx mice. Treatment of TUDCA not only attenuated proteinuria and kidney histological changes, but also ameliorated podocyte and glomeruli injury in diabetic mice, which were associated with reduction of RTN1A and ER stress marker expression in the podocytes of TUDCA-treated mice. In vitro, we showed RTN1A mediates albumin-induced ER stress and apoptosis in human podocytes. A positive feedback loop between RTN1A and CHOP was found leading to an enhanced ER stress in podocytes. Our data suggest that ER stress plays a major role in podocyte injury in DN and RTN1A might be a key regulator of ER stress in podocytes.
我们之前报道过，网蛋白 1A（RTN1A）在介导肾小管细胞内质网（ER）应激中起关键作用，且 RTN1A 的表达与糖尿病肾病（DN）患者的肾功能和肾脏损伤严重程度相关。在这里，我们确定了 RTN1A 和 ER 应激在足细胞损伤和 DN 中的作用。我们使用早期单侧肾切除术（Unx）的 db/db 小鼠作为进行性 DN 的小鼠模型，并使用牛磺熊脱氧胆酸（TUDCA）治疗小鼠，TUDCA 是 ER 应激的特异性抑制剂。我们发现 db/db-Unx 小鼠肾脏中 RTN1A 和 ER 应激标志物的表达增加。TUDCA 的治疗不仅减轻了蛋白尿和肾脏组织学变化，而且改善了糖尿病小鼠的足细胞和肾小球损伤，这与 TUDCA 治疗小鼠足细胞中 RTN1A 和 ER 应激标志物表达的减少有关。在体外，我们表明 RTN1A 介导白蛋白诱导的 ER 应激和人足细胞中的细胞凋亡。发现 RTN1A 和 CHOP 之间存在正反馈环，导致足细胞中的 ER 应激增强。我们的数据表明，ER 应激在 DN 中的足细胞损伤中起主要作用，而 RTN1A 可能是足细胞中 ER 应激的关键调节剂。
