The function of miR-199a-5p/Klotho regulating TLR4/NF-κB p65/NGAL pathways in rat mesangial cells cultured with high glucose and the mechanism.

Anti-aging protein Klotho may confer a renal protective effect via attenuating the nuclear factor-κB (NF-κB) p65 pathways activity. Besides, miR-199a-5p can promote gastric cancer by inhibition of Klotho protein expression. But little is known regarding to the role of miR-199a-5p/Klotho in regulating NF-κB p65 pathways in the pathogenesis of diabetic kidney disease (DKD). Thus, we explored Klotho and miR-199a-5p in terms of Toll-like receptor-4 (TLR4)/NF-κB p65/neutrophil gelatinase associated lipocalin (NGAL) signaling pathways in high glucose cultured mesangial cells (MCs). We found that high glucose increased miR-199a-5p expression, accompanied by the significantly decreased Klotho expression at both mRNA and protein. High glucose also activated TLR4/NF-κB p65/NGAL signaling pathways and promoted the downstream fibrosis and inflammatory reaction. Additionally, inhibition of miR-199a-5p or exogenous addition of Klotho restrained the activity of TLR4/NF-κB p65/NGAL signaling pathways, which in turn suppressed the inflammation and fibrosis in high glucose cultured MCs. This study provides a new basis to elucidate the protection mechanism of anti-aging protein Klotho in diabetic kidney. For the first time, our study prompts that miR-199a-5p can be used as a new therapeutic targets for DKD.