Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

• Main Authors: Yibo Zhuang, Fei Zhao, Jing Liang, Xu Deng, Yue Zhang, Guixia Ding, Aihua Zhang, Zhanjun Jia, Songming Huang
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2017-06-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Albumin; NLRP3 inflammasome; COX-2; PGE2; Proximal tubule cells
• Online Access: http://www.karger.com/Article/FullText/478070

Background/Aims: The activation of NOD-like receptor family, pyrin domain containing3 (NLRP3) inflammasome has been shown to be positively correlated with the severity of proteinuria in chronic kidney disease (CKD) patients. Prostaglandin E2 (PGE2), an important inflammatory mediator, is also involved in various kidney injuries. The aim of the present study was to investigate the involvement of NLRP3 inflammasome and PGE2 synthetic pathway in albumin-induced renal tubular injury. Methods: Murine proximal tubular cells (mPTCs) were treated with albumin to induce cell injury. NLRP3 siRNA and specific COX-2 inhibitor NS398 were used to define their roles in mediating albumin-induced mPTC injury or the activation of COX-2/mPGES-1/PGE2 cascade. Results: In mPCTs, inhibition of NLRP3 by a small interfering RNA (siRNA) blocked albumin-induced kidney injury molecule 1 (KIM-1) upregulation, inflammatory response, and cell apoptosis. Albumin markedly activated cyclooxygenase-2 (COX-2)/ microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway in this cell line, an effect largely abolished by NLRP3 silencing at both mRNA and protein levels. More interestingly, blockade of COX-2 using a specific COX-2 inhibitor NS398 markedly inhibited the upregulation of KIM-1 and inflammatory cytokines, and attenuated cell apoptosis in line with blunted PGE2 release following albumin treatment. Conclusions: The findings suggest that COX-2/mPGES-1/PGE2 axis could be activated by albumin in the proximal tubular cells via a NLRP3 inflammasome-mediated mechanism and could thus contribute to proteinuria-related renal tubular cell injury.