Augmented renal prostacyclin by intrarenal bicistronic cyclo-oxygenase-1/ Prostacyclin synthase gene transfer attenuates renal ischemia-reperfusion injury

BACKGROUND: We elucidated the protective mechanism of increased prostacyclin (PGI2) derived from adenoviral cyclo-oxygenase (COX)-1/prostacyclin synthase (PGIS) (Adv-COPI) gene transfer in rat kidneys with ischemia-reperfusion (I/R) injury. METHODS: We tended to augment PGI2 production by intrarenal arterial Adv-COPI administration with renal venous clamping in female Wistar rats. After Adv-COPI transfection, we evaluated the renal COX-1 and PGIS protein expression and PGI2 and prostaglandin E2 (PGE2) levels in the kidney and renal venous plasma. We evaluated the protective effect of PGI2 on hypoxia/reoxygenation-induced tubular cells injury or I/R kidneys by measuring oxidative stress, necrosis, apoptosis, and autophagy in tubules and kidneys and determining renal function, microcirculation, and accumulation of tubular 4-hydroxynonenal in the kidney in vivo. RESULTS: Adv-COPI treatment selectively augmented COX-1 and PGIS protein expression in the renal proximal and distal tubules and significantly increased PGI2, not PGE2, production in the renal venous plasma and kidney at the baseline level. I/R markedly depressed renal blood flow and increased the production in O2, PGE2, the expression in P47 and Rac-1 expression of two nicotinamide adenine dinucleotide phosphate oxidase subunits, cytosolic cytochrome C release, proapoptotic marker lamin expression, the pathologic appearance of necrosis, apoptosis, and autophagy, and blood urea nitrogen and creatinine levels in the damaged kidneys. Adv-COPI protected distal and proximal tubules against hypoxia/reoxygenation-enhanced oxidative stress and autophagic, apoptotic, and necrotic cell death. Adv-COPI significantly improved renal function by restoring renal blood flow, reducing nicotinamide adenine dinucleotide phosphate oxidase-derived and mitochondria-derived oxidative stress, and necrosis, apoptosis, and autophagy. CONCLUSIONS: Increased PGI2 by Adv-COPI protects the kidney against I/R-induced oxidative stress, necrosis, apoptosis and autophagy.