Augmented Renal Prostacyclin by Intrarenal Bicistronic Cyclo-oxygenase-1/Prostacyclin Synthase Gene Transfer Attenuates Renal Ischemia-Reperfusion Injury

作者：Yang Chih Ching; Chen Kuo Hsin; Hsu Shih Ping; Chien Chiang Ting^*

来源：Transplantation, 2013, 96(12): 1043-1051.

DOI：10.1097/TP.0b013e3182a77e52

• Prostacyclin
• Ischemia-reperfusion
• Kidney
• Oxidative stress
• Programmed cell death

Background. We elucidated the protective mechanism of increased prostacyclin (PGI(2)) derived from adenoviral cyclooxygenase (COX)-1/prostacyclin synthase (PGIS) (Adv-COPI) gene transfer in rat kidneys with ischemia-reperfusion (I/R) injury %26lt;br%26gt;Methods. We tended to augment PGI(2) production by intrarenal arterial Adv-COPI administration with renal venous clamping in female Wistar rats. After Adv-COP1 transfection, we evaluated the renal COX-1 and PGIS protein expression and PGI(2) and prostaglandin E-2 (PGE(2)) levels in the kidney and renal venous plasma. We evaluated the protective effect of PGI(2) on hypoxia/reoxygenation-induced tubular cells injury or I/R kidneys by measuring oxidative stress, necrosis, apoplosis, and autophagy in tubules and kidneys and determining renal function, microcirculation, and accumulation of tubular 4-hydroxynonenal in the kidney in vivo. %26lt;br%26gt;Results. Adv-COPI treatment selectively augmented COX-1 and PGIS protein expression in the renal proximal and distal tubules and significantly increased PGI(2),, not PGE2, production in the renal V enous plasma and kidney at the baseline level. PR markedly depressed renal blood flow and increased the production in O-2(-) PGE(2), the expression in P47 and Rac-1 expression of two nicolinamide adenine dinucleolide phosphate oxidase subunits, cylosolic cylochrome C release, proapoptotic marker lamin expression, the pathologic appearance of necrosis, apoptosis, and autophagy, and blood urea nitrogen and creatininc 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 %26lt;br%26gt;Conclusions. Increased PGI2 by Adv-COPI protects the kidney against PR-induced oxidative stress, necrosis, apoptosis and autophagy.

• 出版日期2013-12-27