Department of Nephrology, Second People's Hospital, The First Affiliated Hospital of Shenzhen University, 518000, Shenzhen, Guangdong Province, P.R. China.
Department of Pathophysiology, China Medical University, 110001, Shenyang, Liaoning Province, P.R. China.
Cell Death Dis. 2020 Jul 17;11(7):544. doi: 10.1038/s41419-020-2731-6.
Zinc transporter 8 (ZnT8) transports zinc ions for crystallization and storage of insulin in pancreatic beta-cells and ZnT8 dysfunction is involved in pathogenesis of diabetes. The current study aimed to investigate whether ZnT8 has effects in pathophysiology of diabetic kidney disease (DKD) by using animal models for diabetes, including STZ-induced diabetic, db/db, ZnT8-KO, ZnT8-KO-STZ and ZnT8-KO-db/db mice. Results demonstrated that urine albumin to creatinine ratio and epithelial-to-mesenchymal transition (EMT) were increased in kidneys of ZnT8-KO-STZ and ZnT8-KO-db/db mice compared with C57BL/6 J and ZnT8-KO mice, while serum TGF-β1, IL-6, and TNF-α levels were elevated in parallel. In kidneys of mice intercrossed between ZnT8-KO and STZ-induced diabetic or db/db mice, these three inflammatory factors, ACR and EMT were also found to be increased compared with C57BL/6J, db/db and ZnT8-KO mice. Furthermore, ZnT8 up-regulation by hZnT8-EGFP reduced the levels of high glucose (HG)-induced EMT and inflammatory factors in normal rat kidney tubular epithelial cell (NRK-52E cells). Expression of phosphorylated Smad2/Smad3 was up-regulated after HG stimulation and further enhanced by ZnT8 siRNA but down-regulated after hZnT8-EGFP gene transfection. The current study thus provides the first evidence that ZnT8 protects against EMT-tubulointerstitial fibrosis though the restrain of TGF-β1/Smads signaling activation in DKD.
锌转运蛋白 8（ZnT8）将锌离子转运到胰腺β细胞中用于胰岛素的结晶和储存，而 ZnT8 功能障碍与糖尿病的发病机制有关。本研究旨在通过使用糖尿病动物模型，包括 STZ 诱导的糖尿病、db/db、ZnT8-KO、ZnT8-KO-STZ 和 ZnT8-KO-db/db 小鼠，研究 ZnT8 是否对糖尿病肾病（DKD）的病理生理学有影响。结果表明，与 C57BL/6J 和 ZnT8-KO 小鼠相比，ZnT8-KO-STZ 和 ZnT8-KO-db/db 小鼠肾脏中的尿白蛋白与肌酐比值和上皮间质转化（EMT）增加，而血清 TGF-β1、IL-6 和 TNF-α 水平也同时升高。在 ZnT8-KO 与 STZ 诱导的糖尿病或 db/db 小鼠杂交的小鼠肾脏中，与 C57BL/6J、db/db 和 ZnT8-KO 小鼠相比，这三种炎症因子、ACR 和 EMT 也发现增加。此外，hZnT8-EGFP 上调 ZnT8 可降低高糖（HG）诱导的正常大鼠肾近端小管上皮细胞（NRK-52E 细胞）中 EMT 和炎症因子的水平。HG 刺激后磷酸化 Smad2/Smad3 的表达上调，ZnT8 siRNA 进一步增强，而 hZnT8-EGFP 基因转染后下调。因此，本研究首次提供证据表明，ZnT8 通过抑制 TGF-β1/Smads 信号通路的激活来防止 EMT-肾小管间质纤维化，从而在 DKD 中发挥保护作用。
