PTPN2 improved renal injury and fibrosis by suppressing STAT-induced inflammation in early diabetic nephropathy.

Ya Li,Ming Song,Ming Zhong,Guokai Shang,Fangfang Chen,Wei Zhang,Zhihao Wang,Lu Han,Huimin Zhou,Di Wang,Yulin Li

doi:10.1111/jcmm.14304

Abstract

Diabetic nephropathy (DN) is a chronic inflammatory disease triggered by disordered metabolism. Recent studies suggested that protein tyrosine phosphatase non‐receptor type 2 (PTPN2) could ameliorate metabolic disorders and suppress inflammatory responses. This study investigated PTPN2's role in modulating DN and the possible cellular mechanisms involved. In a mouse model combining hyperglycaemia and hypercholesterolaemia (streptozotocin diabetic, ApoE‐/‐ mice), mice showed severe insulin resistance, renal dysfunction, micro‐inflammation, subsequent extracellular matrix expansion and decreased expression of PTPN2. We found that mice treated with PTPN2 displayed reduced serum creatinine, serum BUN and proteinuria. PTPN2 gene therapy markedly attenuated metabolic disorders and hyperglycaemia. In addition, PTPN2 gene transfer significantly suppressed renal activation of signal transducers and activators of transcription (STAT), STAT‐dependent pro‐inflammatory and pro‐fibrotic genes expression, and influx of lymphocytes in DN, indicating anti‐inflammatory effects of PTPN2 by inhibiting the activation of STAT signalling pathway in vivo. Furthermore, PTPN2 overexpression inhibited the high‐glucose induced phosphorylation of STAT, target genes expression and proliferation in mouse mesangial and tubuloepithelial cells, suggesting that the roles of PTPN2 on STAT activation was independent of glycaemic changes. Our results demonstrated that PTPN2 gene therapy could exert protective effects on DN via ameliorating metabolic disorders and inhibiting renal STAT‐dependent micro‐inflammation, suggesting its potential role for treatment of human DN.

Highlights

Diabetic nephropathy (DN), which is characterized by glomerular and tubular disorders, is a major micro‐vascular complication[1] and accounts for more than 50% of all cases of end‐stage renal diseaseYa Li and Huimin Zhou have contributed to this work.(ESRD).[2]
Among the inflammatory genes induced by HG in renal cells, we investigated the role of protein tyrosine phosphatase non‐recep‐ tor type 2 (PTPN2) on the expression of classical signal trans‐ ducers and activators of transcription (STAT)‐dependent genes, including adhesion molecules (ICAM‐1), cytokines (TNF‐α and IL‐6) and chemokines (MCP‐1)
We found that diabetic mice developed albuminuria, mesangial matrix expansion, tubulointerstitial fibrosis and mac‐ rophage influx and showed a decreased renal function; PTPN2 was markedly down‐regulated in diabetic mice, with increased activa‐ tion of STAT and STAT‐dependent pro‐inflammatory and pro‐fibro‐ genic cytokines; PTPN2 gene therapy could exert protective effects on DN via ameliorating metabolic disorders and inhibiting renal micro‐inflammation

Summary

| INTRODUCTION

Diabetic nephropathy (DN), which is characterized by glomerular and tubular disorders, is a major micro‐vascular complication[1] and accounts for more than 50% of all cases of end‐stage renal disease. PTPN2, one of 17 intracellular and non‐receptor PTPs, was originally cloned from a human T‐cell cDNA library.[16] It is ubiq‐ uitously expressed (eg intestinal and renal epithelium, fibroblasts, hepatocytes).[17]. Evidence is emerging for the involvement of PTPN2 in the onset and progression of inflammatory diseases, such as Crohn's dis‐ ease, T1DM and rheumatoid arthritis.[14,16,18,19]. These results suggest the important role of PTPN2 in metabolic diseases and in‐ flammation, it remains unknown whether PTPN2 contributes to the progression of DN. We aimed to explore whether PTPN2 gene therapy could im‐ prove DN by regulating systemic metabolic disorders and inhibiting local inflammation in kidney

| MATERIALS AND METHODS

Findings

| DISCUSSION