PIAS1 alleviates diabetic peripheral neuropathy through SUMOlation of PPAR-\u03b3 and miR-124-induced downregulation of EZH2/STAT3

Zixin Hou,Huan Yang,Ji Chen,Xiaoling Hu,Fengrui Yang

doi:10.1038/s41420-021-00765-w

Abstract

Diabetic peripheral neuropathy (DPN) is a frequently occurring chronic complication of diabetes. In this study, we aim to explore the regulatory mechanism of protein inhibitor of activated STAT1 (PIAS1) in DPN in terms of autophagy and apoptosis of Schwann cells. The SUMOlation of PPAR-γ by PIAS1 was examined, and ChIP was performed to verify the binding of PPAR-γ to miR-124 promoter region. Dual-luciferase gene reporter assay was used to validate the binding affinity between miR-124 and EZH2/STAT3. Following loss‐ and gain‐of-function experiments, in vitro assays in high glucose-treated Schwann cells (SC4) and in vivo assays in db/db and ob/ob mice were performed to detect the effects of PIAS1 on autophagy and apoptosis of Schwann cells as well as symptoms of DPN by regulating the PPAR-γ-miR-124-EZH2/STAT3. The expression of PIAS1, PPAR-γ, and miR-124 was downregulated in the sciatic nerve tissue of diabetic mice. PIAS1 enhanced the expression of PPAR-γ through direct binding and SUMOlation of PPAR-γ. PPAR-γ enhanced the expression of miR-124 by enhancing the promoter activity of miR-124. Furthermore, miR-124 targeted and inversely modulated EZH2 and STAT3, promoting the autophagy of Schwann cells and inhibiting their apoptosis. In vivo experiments further substantiated that PIAS1 could promote the autophagy and inhibit the apoptosis of Schwann cells through the PPAR-γ-miR-124-EZH2/STAT3 axis. In conclusion, PIAS1 promoted SUMOlation of PPAR-γ to stabilize PPAR-γ expression, which upregulated miR-124 to inactivate EZH2/STAT3, thereby inhibiting apoptosis and promoting autophagy of Schwann cells to suppress the development of DPN.

Highlights

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus [1]
Fasting blood glucose was measured and peroxisome proliferator-activated receptor γ (PPAR-γ) oral glucose tolerance test (OGTT) was carried out to confirm the We investigated whether protein inhibitor of activated STAT1 (PIAS1) could regulate the SUMOylation of establishment of diabetic models in db/db mice and ob/ob mice PPAR-γ in DPN
These results suggest that miR-124 can inhibit the expression of Enhancer of zeste homolog 2 (EZH2) and Signal transducer and activator of transcription 3 (STAT3), thereby inhibiting apoptosis induced by high glucose and promoting autophagy of Schwann cells

Summary

INTRODUCTION

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus [1]. The pathogenesis of DPN is a complicated process involving multiple factors [4]; and, notably, injury to Schwann cells has been highlighted in the progression of DPN [5,6,7]. A previous review has indicated that Schwann cell apoptosis is induced by high glucose and is involved in the pathogenesis of DPN [8]. Cheng et al stated that hyperglycemia induces oxidative stress and inflammatory responses that damage nerve tissue, and that Schwann cell dysfunction could further promote the progression of DPN [6]. PPAR-γ could induce differentiation of Schwann cells, thereby regulating injury and regeneration of peripheral nerves [14]. The protein expression of PIAS1 was decreased in SC4 cells treated with high glucose (Fig. 1F).

RESULTS

DISCUSSION

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