The Protective Effects of Protease Inhibitor MG-132 on Sepsis-Induced Acute Kidney Injury and Its Mechanisms

Abstract

MG-132 is an aldehyde peptide proteasome inhibitor, which reduces the inflammatory response and exerts a protective effect on severe acute pancreatitis and associated lung injury of rats. However, the involvement of MG-132 in sepsis-induced acute kidney injury (AKI) and the underlying mechanisms remain unknow. In this study, SD rats were employed to induce sepsis by cecal ligation and puncture (CLP) method and then divided into control, sham, CLP, and CLP + MG-132. Histopathology observation was detected by hematoxylin and eosin staining. The levels of biomarkers representing renal function such as serum creatinine (Scr), blood urea nitrogen (BUN), serum cystatin C (Scys C), and indicators of AKI such as Kim-1, IL-18, α glutathione S-traferase (α-GST) and albumin were measured by ELISA. Western blot and immunohistochemistry were performed to measure Testican-1. In order to assess the role of Testican-1, the expression of β-catenin, c-myc and cyclinD1 were evaluated by western blot. The results indicated that the levels of SCr, BUN, Scys C, KIM-1, IL-18, GST-α and albumin were decreased after MG-132 treatment compared with CLP group. And both pathological injury and W/D ratio were obviously improved in the CLP + MG- 132 group. Furthermore, the level of Testican-1 increased in the CLP group while a decreased presented in the CLP + MG-132 group. The expression of β-catenin, c-myc and cyclinD1 were downregulated in the CLP + MG-132 group compared to the CLP group. Our findings suggested that MG-132 can protect against AKI via inhibiting Testican-1 through the Wnt/β-catenin pathway MG-132 served as a novel biomarker and therapeutic regimen for sepsis-induced AKI.