Mitochondrial oxidative stress activates COX-2/mPGES-1/PGE2 cascade induced by albumin in renal proximal tubular cells

// Yibo Zhuang 1, 2, 3, * , Chenhu Wang 1, 2, 3, * , Chunfeng Wu 1, 2, 3 , Dan Ding 1, 2, 3 , Fei Zhao 1, 2, 3 , Caiyu Hu 1, 2, 3 , Wei Gong 1, 2, 3 , Guixia Ding 1, 2, 3 , Yue Zhang 1, 2, 3 , Lihong Chen 1, 2, 3 , Guangrui Yang 1, 2, 3 , Chunhua Zhu 1, 2, 3 , Aihua Zhang 1, 2, 3 , Zhanjun Jia 1, 2, 3 and Songming Huang 1, 2, 3 1 Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China 2 Jiangsu Key Laboratory of Pediatrics, Nanjing 210029, China 3 Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China * These authors equally contributed to this work Correspondence to: Songming Huang, email: smhuang@njmu.edu.cn Keywords: albumin; mitochondrial oxidative stress; COX-2; PGE2; proximal tubular cells Received: November 19, 2017      Accepted: January 04, 2018      Published: January 12, 2018 ABSTRACT COX-2/mPGES-1/PGE2 cascade is of importance in the pathogenesis of kidney injury. Meanwhile, recent studies documented a detrimental role of mitochondrial oxidative stress in kidney diseases. The present study was undertaken to investigate the role of mitochondrial oxidative stress in albumin-induced activation of COX-2/mPGES-1/PGE2 cascade in renal proximal tubular cells. Following albumin overload in mice, we observed a significant increase of oxidative stress and mitochondrial abnormality determined by transmission electron microscope, which was attenuated by the administration of MnTBAP, a mitochondrial SOD2 mimic. More interestingly, albumin overload-induced upregulation of COX-2 and mPGES-1 at mRNA and protein levels was largely abolished by MnTBAP treatment in mice. Meanwhile, urinary PGE2 excretion was also blocked by MnTBAP treatment. Furthermore, mouse proximal tubule epithelial cells (mPTCs) were treated with albumin. Similarly, COX-2/mPGES-1/PGE2 cascade was significantly activated by albumin in dose- and time-dependent manners, which was abolished by MnTBAP treatment in parallel with a blockade of oxidative stress. Collectively, the findings from current study demonstrated that mitochondrial oxidative stress could activate COX-2/mPGES-1/PGE2 cascade in proximal tubular cells under the proteinuria condition. Mitochondrial oxidative stress/COX-2/mPGES-1/PGE2 could serve as the important targets for the treatment of proteinuria-associated kidney injury.