Apelin inhibited epithelial\u2212mesenchymal transition of podocytes in diabetic mice through downregulating immunoproteasome subunits \u03b25i

Jiming Yin,Bin Li,Jing Chang,Xiangjun Zeng,Yangjia Wang,Ying Jiang,Jia Zhang,Song Lai,Huihua Li,Yu Liu

doi:10.1038/s41419-018-1098-4

Abstract

The epithelial−mesenchymal transition (EMT) of podocytes had been reported to be involved in the glomerular fibrosis in diabetic kidney diseases, which was regulated by TGFβ and NFκB pathways. And apelin, an adipokine which is upregulated in diabetic kidney diseases, was reported to be negatively correlated to TGFβ in polycystic kidney disease and attenuate EMT in renal tubular cells. Therefore, it is hypothesized that apelin might inhibit the EMT of podocytes through downregulating the expression and activation of TGFβ/Smad pathway in diabetic kidney diseases. The results showed that apelin in glomeruli of diabetic mice were increased and exogenous apelin inhibited the EMT of podocytes in diabetic mice, which were accompanied with the decreased expression of proteasome subunits β5i. The results from β5iKO mice confirmed that the inhibiting effects of apelin on EMT of podocytes in diabetic mice were dependent on β5i. The results from culture podocytes showed that apelin decreased the degradation of pIκB and promoted the translocation of IκB into nucleus through decreasing the expression of β5i, which would inhibit the promoting effects of NFκB on expression of TGFβ and followed by decreased activation of Smad pathway and EMT in podocytes. In conclusion, apelin might act as an EMT suppressor for podocytes to decrease the process of glomerular fibrosis in diabetic mice.

Highlights

Emerging evidence indicated that podocytes would go epithelial−mesenchymal transition (EMT) in diabetic conditions by losing expression of highly specialized markers of podocyte such as nephrin, synapotodin, zonula occludens-1 (ZO-1), and Wilms’ tumor 1 (WT 1) and acquiring expression of new mesenchymal markers such as α-Smooth Muscle Actin (α-SMA), type I collagen (Col-I), type IV collagen (Col-IV), and fibronectin (FN)[1,2,3]
The results showed that transcriptions of α-SMA, fibronectin, and collagen1α mRNAs were induced by high glucose to 1.2, 1.7, and 1.3 folds in podocytes compared to the control group, while apelin reversed these transcriptions to 0.5–0.7 folds in podocytes compared to the control group (Fig. 5a–c)
Apelin, which was upregulated in diabetic mice (Fig. 1), alleviated glomerular fibrosis and decreased expression of EMT markers, such as α-SMA, collagen[1], αfibronectin (Fig. 3), and TGFβ (Fig. 4) in diabetic mice

Summary

Introduction

Emerging evidence indicated that podocytes would go epithelial−mesenchymal transition (EMT) in diabetic conditions by losing expression of highly specialized markers of podocyte such as nephrin, synapotodin, zonula occludens-1 (ZO-1), and Wilms’ tumor 1 (WT 1) and acquiring expression of new mesenchymal markers such as α-Smooth Muscle Actin (α-SMA), type I collagen (Col-I), type IV collagen (Col-IV), and fibronectin (FN)[1,2,3]. EMT of podocytes would result in glomerular fibrosis in diabetic kidney diseases (DKD)[4]. Previous studies indicated that Apelin, an adipokine which is upregulated in DKD, was negatively correlated to renal fibrosis and TGFβ in polycystic kidney disease[5]. Apelin was reported to attenuate EMT in renal tubular cells[6]. Is apelin capable of inhibiting glomerular fibrosis induced by diabetes mellitus through reducing EMT of podocytes?

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Conclusion