Abstract

Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD). To date, mounting evidence has shown that inflammation may contribute to the pathogenesis of DN. Recent reports have shown that proteasome inhibitors display cytoprotection by reducing the phosphorylation of Akt, a serine/threonine kinase, plays a critical role in cellular survival and metabolism and can crosstalk with inflammation. Therefore, we hypothesized that MG132, specific proteasome inhibitor, could provide renoprotection by suppressing Akt-mediated inflammation in DN. In vivo, male Sprague-Dawley rats were divided into normal control group (NC), diabetic nephropathy group (DN), DN model plus MG132 treatment group (MG132), and DN model plus deguelin treatment group (Deguelin)(deguelin, a specific inhibitor of Akt). In vitro, a human glomerular mesangial cell lines (HMCs) was exposed to 5.5 mmol/L glucose (CON), 30 mmol/L glucose (HG), 30 mmol/L glucose with 0.5 umol/L MG132 (MG132) and 30 mmol/L glucose with 5 umol/L deguelin (Deguelin). Compared with NC, DN showed a significant increase in the urinary protein excretion rate and inflammatory cytokines, as well as p-Akt. Compared with CON, HMCs co-cultured with HG was notably proliferated, which is in accord with α-smooth muscle actin (α-SMA) expression. These alterations were inhibited by administration of MG132 or deguelin. In conclusion, MG132 significantly inhibits the development of DN by regulating Akt phosphorylation-mediated inflammatory activation.

Highlights

  • Diabetic nephropathy (DN) is one of the major causes of microvascular complications of diabetes mellitus (DM) and the leading cause of chronic and end-stage-renal disease worldwide (CKD and end-stage renal disease (ESRD), respectively)[1]

  • Compared to the DN group, treatment with MG132 or deguelin markedly lowed the increase in kidney weight/body weight index (KI) and Glu, especially at 8 and 12 weeks (P < 0.05), but had no effect on the metabolism of Scr, TG, and total cholesterol (TC)

  • This study demonstrated that the proteasome inhibitor MG132 had a preventative effect on impaired renal function induced by persistent high glucose

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Summary

Introduction

Diabetic nephropathy (DN) is one of the major causes of microvascular complications of diabetes mellitus (DM) and the leading cause of chronic and end-stage-renal disease worldwide (CKD and ESRD, respectively)[1]. Major hallmarks of DN include accumulation of extracellular matrix (ECM) proteins, such as collagens and mesangial expansion in the kidney glomerular and tubular compartments, which contribute to renal failure in diabetes[3,4,5]. Previous studies have reported the importance of the PI3K/Akt pathway, an important regulator of growth and inflammation, in inflammation-mediated diseases, such as rheumatoid arthritis (RA)[9] and psoriasis[10]. We aimed to determine the effects of high glucose on the development of inflammation and mesangial cell proliferation, as well as mesangial matrix expansion. MG132, specific proteasome inhibitor, prevents damage by inhibiting inflammatory process by regulating Akt and exerts a marked renoprotective effect

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