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  • Title: 1,25(OH)2D3 provides protection against diabetic kidney disease by downregulating the TLR4-MyD88-NF-κB pathway.
    Author: Liu P, Li F, Xu X, Li S, Dong X, Chen L, Bai B, Wang Y, Qiu M, Dong Y.
    Journal: Exp Mol Pathol; 2020 Jun; 114():104434. PubMed ID: 32240615.
    Abstract:
    The over-activation of Toll-like receptors (TLRs) is a typical immune response to injury. Previous work has suggested that controlling the over-activation of TLR4-MyD88-NF-κB may represent a new therapeutic option for diabetic kidney disease (DKD). 1,25(OH)2D3 has also been shown to exert a protective effect on DKD, although the mechanism involved has yet to be elucidated. The aim of this study was to investigate whether 1,25(OH)2D3 protects against DKD by down-regulating the innate immune TLR-NF-κB pathway. NRK-52E cells were cultured under normal or high-glucose conditions. We then used siRNA to knock down TLR4 expression under high-glucose conditions. NRK-52E cells cultured under high-glucose conditions, and streptozotocin (STZ)-induced diabetic rats, were treated with different doses of 1,25(OH)2D3 and used as in vitro and in vivo models, respectively. Renal biochemical indicators were then measured to evaluate the influence of 1,25(OH)2D3 treatment on DKD in diabetic rats. Histological analysis was also performed to determine the extent of infiltration by inflammatory cells and tubulointerstitial fibrosis. Using RT-qPCR, western blotting, immunohistochemistry and immunofluorescence, we determined the expression levels of TLR4, MyD88, NF-κB p65, MCP-1 and α-SMA to investigate whether 1,25(OH)2D3 could reduce the development of tubulointerstitial fibrosis. Knocking down TLR4 abolished the tubulointerstitial fibrosis caused by high-glucose conditions. High doses of 1,25(OH)2D3 consistently reduced the expression of TLR4-MyD88-NF-κB in NRK-52E cells. Moreover, high doses of 1,25(OH)2D3 had an obvious protective effect on kidney injury and inhibited the infiltration of inflammatory cells and tubulointerstitial fibrosis in diabetic rats. In conclusion, high doses of 1,25(OH)2D3 protected against tubulointerstitial fibrosis both in vitro and in vivo by downregulating the expression of TLR4-MyD88-NF-κB.
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