SOCS2 overexpression alleviates diabetic nephropathy in rats by inhibiting the TLR4/NF-κB pathway.

Suxia Yang,Shiying Wang,Jun Shi,Xinxin Zhao,Junwei Zhang

doi:10.18632/oncotarget.20434

Abstract

Suppressor of cytokine signaling 2 (SOCS2) was reported to be involved in the development of Diabetic Nephropathy (DN). However, its underlying mechanism remains undefined. Western blot was carried out to determine the expressions of SOCS2, Toll-like receptors 4 (TLR4) and nuclear factor kappa B (NF-κB) pathway-related proteins in DN patients, streptozotocin (STZ)-induced DN rats and high glucose (HG)-stimulated podocytes. The effects of SOCS2 overexpression on renal injury, the inflammatory cytokines production, renal pathological changes, apoptosis and the TLR4/NF-κB pathway in DN rats or HG-stimulated podocytes were investigated. TLR4 antagonist TAK-242 and NF-κB inhibitor PDTC were used to confirm the functional mechanism of SOCS2 overexpression in HG-stimulated podocytes. SOCS2 was down-regulated, while TLR4 and NF-κB were up-regulated in renal tissues of DN patients and DN rats. Ad-SOCS2 infection alleviated STZ-induced renal injury and pathological changes and inhibited STZ-induced IL-6, IL-1β and MCP-1 generation and activation of the TLR4/NF-κB pathway in DN rats. SOCS2 overexpression attenuated apoptosis, suppressed the inflammatory cytokines expression, and inactivated the TLR4/NF-κB pathway in HG-stimulated podocytes. Suppression of the TLR4/NF-κB pathway enhanced the inhibitory effect of SOCS2 overexpression on apoptosis and inflammatory cytokines expressions in HG-stimulated podocytes. SOCS2 overexpression alleviated the development of DN by inhibiting the TLR4/NF-κB pathway, contributing to developing new therapeutic strategies against DN.

Highlights

Diabetic nephropathy (DN) is a complicated diabetic disease that can develop into a progressive fibrosing kidney disease [1]
The western blot results showed that the level of Suppressor of cytokine signaling 2 (SOCS2) was significantly lower and Toll-like receptors 4 (TLR4) was dramatically higher in renal tissues of Diabetic Nephropathy (DN) patients (Figure 1A) and DN rats (Figure 1B) than that in control groups
These findings revealed that SOCS2, TLR4 and nuclear factor kappa B high glucose (HG) (NF-κB) may be involved in the development of DN

Summary

Introduction

Diabetic nephropathy (DN) is a complicated diabetic disease that can develop into a progressive fibrosing kidney disease [1]. Despite improved prognosis in the last few years, DN has become a leading cause of end-stage renal disease (ESRD) and even mortality in the industrialized world, and its escalating incidence and prevalence in parallel with the pandemic of type 2 diabetes are great threats to life [2, 3]. Many studies suggest that DN patients are usually accompanied with some pathological signs, such as thicker glomerular basement membrane, renal hypertrophy, progressive glomerulosclerosis and mesangial expansion [4]. DN is historically regarded as a largely nonimmune disease, evidence from recent experimental and clinical studies indicates that chronic inflammation exerts a crucial role in DN pathogenesis and progression [5]. The treatment for DN is important to improve patients’ prognosis, further researches concerning the potential mechanism of intrarenal inflammation in aggravating DN are essential to be investigated, which may provide novel therapeutic targets for anti-infammatory strategies against DN

Methods

Results

Conclusion