Vitamin D protects glomerular mesangial cells from high glucose-induced injury by repressing JAK/STAT signaling

Yiya Yang,Yinyin Chen,Kanghan Liu,Yuting Lei,Congjun Yang,Shuangshuang Fu,Yumei Liang

doi:10.1007/s11255-020-02728-z

Yiya Yang, Yinyin Chen + Show 5 more

Open Access

https://doi.org/10.1007/s11255-020-02728-z

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Abstract

AimHigh glucose (HG) induces the production of transforming growth factor (TGF)-β and reactive oxygen species, which further activates JAK/STAT signaling and promotes the synthesis of matrix proteins, contributes to the pathophysiological processes of diabetic nephropathy. This study aims to investigate the protection role of vitamin D (VD) in the kidney in high glucose condition.MethodsRat glomerular mesangial cells were cultured in high glucose medium, with or without VD or VD receptor (VDR) siRNAs treatment. The levels of TGF-β and fibronectin were detected by qRT-PCR, immunoblotting and enzyme-linked immunosorbent assay (ELISA). The levels of phosphorylated JAK2, STAT1 and STAT3, and JAK/STAT signaling downstream genes were examined by immunoblotting and qRT-PCR.ResultsIn rat glomerular mesangial cells, VD treatment can repress the tyrosine phosphorylation of JAK2, STAT1 and STAT3. VD inhibited TGF-β and fibronectin expression which was rescued by vitamin d receptor (VDR) siRNA and STATs inhibitor perficitinib. The JAK/STAT signaling downstream protein coding genes including SOCS1, SOCS3 and type IV collagen were repressed by VD. Meanwhile, the expression of non-coding RNAs such as miR-181a, miR-181b, was repressed by VD, and the expression of miR-34a and Let-7b was upregulated by VD.ConclusionVitamin D (VD) treatment inhibits the function of HG on fibronectin production through regulating JAK/STAT pathway. These results provide direct evidences that VD protects glomerular mesangial cells from high glucose-induced injury through repressing JAK/STAT signaling, which has the potential for clinical DN treatment.

Highlights

Diabetic nephropathy (DN) is a common complication usually found in patients with diabetes mellitus (DM), which is accounting for chronic renal failure [1]
When VD receptor (VDR) was knocked down by Small interfering RNA (siRNA), the effect of vitamin D (VD) on reactive oxygen species (ROS) repression was partially inhibited. These results indicated that VD/VDR signaling play protective roles in glomerular mesangial cells in high glucose environment
ROS can stimulate the activity of STAT kinases and the activation of the JAK/STAT signaling cascade further stimulates excessive proliferation and growth of glomerular mesangial cells, and the matrix proteins expression, contributing to diabetic nephropathy [6, 7]

Summary

Introduction

Diabetic nephropathy (DN) is a common complication usually found in patients with diabetes mellitus (DM), which is accounting for chronic renal failure [1]. It is reported that abnormal renal hemodynamics, hyperglycemia-induced metabolic disorders, and the imbalance of vasoactive substances contribute to the development of DN, the underlying mechanisms for diabetic nephropathy are still not Numerous evidences indicate that hyperglycemia can induce an increase of transforming growth factor-β1 (TGF-β) expression in cultured mesangial cells and diabetic mouse models [8,9,10]. International Urology and Nephrology (2021) 53:1247–1254 and interstitial fibrosis, and reduced the expression of many ECM genes including fibronectin and type IV collagen in diabetic mice [15, 16]. A significant increase of fibronectin was reported in most types of glomerulopathy including DN, which contributes to aberrant thickening of glomerular basement membranes and excessively amassing of mesangial matrices [17,18,19]

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