Abstract
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.
Highlights
Diabetic kidney disease (DKD, previously termed as diabetic nephropathy) is the most common cause of chronic kidney failure and end stage kidney disease[1,2]
Fasting blood glucose (FBG) levels in STZ-induced and Zinc transporter 8 (ZnT8)-KO-STZ diabetic mice were significantly higher than controls
STZ and ZnT8-KO-db/db mice and NRK-52E cells, we have performed in vivo and in vitro experiments to investigate the effects of ZnT8 on epithelial-to-mesenchymal transition (EMT)-tubulointerstitial fibrosis
Summary
Diabetic kidney disease (DKD, previously termed as diabetic nephropathy) is the most common cause of chronic kidney failure and end stage kidney disease[1,2]. Zhang et al Cell Death and Disease (2020)11:544 are important in the pathogenesis of DKD. Several inflammatory cytokines such as tumor necrosis factoralpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF-β1) are found to be associated with glomerular and tubulointerstitial damage in the progresses of DKD7–12. ZnT8 has genetic, epigenetic and biological effects in the pathogenesis of diabetes[16]. Genetic association studies, including ours have demonstrated that the common single nucleotide polymorphisms in the SLC30A8 gene confer the risk susceptibility to type 2 diabetes (T2DM), while the rare loss-of-function variants in the gene have protective effects in the disease[20,21]. Based upon what described above, we have a hypothesis that ZnT8 may play an important role in the pathogenesis of DKD
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