Effects of ZnT8 on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis in diabetic kidney disease

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.

Knockdown of the Long Noncoding RNA LUCAT1 Inhibits High-Glucose-Induced Epithelial-Mesenchymal Transition through the miR-199a-5p–ZEB1 Axis in Human Renal Tubular Epithelial Cells

“…Additionally, the knockdown of this lncRNA inhibited the HG-induced phosphorylation of SMAD3. Several researchers have already suggested that the inhibition of SMAD3 phosphorylation may prevent HG-induced EMT [21,22]. Our results corroborated those studies, suggesting that the knockdown of LUCAT1 inhibited the EMT of HG-treated HK-2 cells.…”

Optimizing diabetic kidney disease animal models: Insights from a meta‐analytic approach

“…The graph illustrates that changes in lipid metabolism are also proportional to the dose and number of doses given. In addition, only minor renal lesions such as mesangial matrix expansion and basement membrane thickening were observed 16,29,30 . As can be seen from Table 3, maternal obesity aggravated both diabetic milieus and renal dysfunction in the offspring, accompanied by renal fibrosis and renal oxidative stress, which may indicate a potential approach to establishing novel DKD models 31 .…”

“…Zinc transporter 8 (ZnT8) transports zinc ions for crystallization and storage of insulin in pancreatic beta‐cells. ZnT8‐KO male mice were subsequently intercrossed with female db/db mice to generate ZnT8‐KO‐db/db mice, causing a more severe type2 DM along with insulin resistance 16 …”

“…ZnT8-KO male mice were subsequently intercrossed with female db/db mice to generate ZnT8-KO-db/db mice, causing a more severe type2 DM along with insulin resistance. 16 KK mice were developed from Kasukabe mice by K. Kondo in 1957 and exhibit insulin resistance and obesity, with albuminuria at 10 to 15 weeks of age. The A y gene not only affects the hair color of mice, but also causes metabolic disorders, which manifest as obesity, hyperglycemia, lipid metabolism disorders and hyperinsulinemia.…”

Research progress of endothelial‐mesenchymal transition in diabetic kidney disease

“…This EndMT induced by TGF‐β through MAPK and AKT is called Smad‐independent signalling pathway (Figure 1 ). 38 , 39 Note that the Smad‐dependent and Smad‐independent pathways can coordinate the regulation of EndMT. For example, ERK MAPK crosstalks with the Smad‐dependent signalling pathway through phosphorylation of Smad2/3.…”