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.
Highlights
Proteinuria plays an established role in mediating renal tubular injury and is viewed as a causative factor in promoting the progression of kidney diseases [1, 2]
Activation of COX-2/membrane associated PGE synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) cascade by albumin overload was blocked by MnTBAP in mice
By Quantitative real-time PCR (qRT-PCR), we observed a selective upregulation of COX-2 and mPGES-1 but not COX-1, membrane associated PGE synthase-2 (mPGES-2), and cytosolic PGE2 synthase (cPGES) (Figure 2A–2E)
Summary
Proteinuria plays an established role in mediating renal tubular injury and is viewed as a causative factor in promoting the progression of kidney diseases [1, 2]. Kidney is a major source of prostaglandins (PGs) including PGE2, PGD2, PGI2, PGF2α, and thromboxane A2 (TXA2). Blockade of COX-2 or PGE2 receptors of EP1 and EP4 resulted in significant protection against diabetic kidney injury [19]. In another proteinuric animal model induced by adriamycin, the overexpression of COX-2 in podocytes remarkably worsened kidney damage [20]. All of these data suggest a critical role of the COX-2/mPGES-1/PGE2 cascade in mediating kidney injury
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