1 Bureau of Planning, Department of Health, Executive Yuan, Taipei, Taiwan. 2 Department of Internal Medicine, National Yang-Ming University, Taipei, Taiwan. 3 Department of General Surgery, Far-East Memory Hospital, New Taipei City, Taiwan. 4 Department of Internal Medicine, Far-East Memory Hospital, New Taipei City, Taiwan. 5 Department of Life Science, National Taiwan Normal University, Taipei, Taiwan. 6 Address correspondence to: Chiang-Ting Chien, Ph.D., Department of Life Science, National Taiwan Normal University, No. 88, Section 4, Tingzhou Road, Taipei City 11677, Taiwan or Shih-Ping Hsu, M.D., Ph.D., Department of Internal Medicine, Far-East Memory Hospital, No. 21, Section 2, Nanya S. Road, Banciao District, New Taipei City 220, Taiwan.
Transplantation. 2013 Dec 27;96(12):1043-51. doi: 10.1097/TP.0b013e3182a77e52.
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.
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.
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.
Increased PGI2 by Adv-COPI protects the kidney against I/R-induced oxidative stress, necrosis, apoptosis and autophagy.
我们阐明了腺病毒环氧化酶（COX）-1/前列环素合酶（PGIS）（Adv-COPI）基因转移增加前列腺素 I2（PGI2）在肾缺血再灌注（I/R）损伤中的保护机制。
我们倾向于通过肾内动脉 Adv-COPI 给药并夹闭肾静脉来增加肾内 PGI2 的产生。在 Adv-COPI 转染后，我们评估了肾脏 COX-1 和 PGIS 蛋白表达以及肾脏和肾静脉血浆中的 PGI2 和前列腺素 E2（PGE2）水平。我们通过测量肾小管和肾脏中的氧化应激、坏死、凋亡和自噬以及确定肾功能、微血管和肾小管 4-羟壬烯醛在体内的积聚来评估 PGI2 对缺氧/复氧诱导的肾小管细胞损伤或 I/R 肾脏的保护作用。
Adv-COPI 处理选择性地增加了肾近端和远端小管中的 COX-1 和 PGIS 蛋白表达，并在基线水平上显著增加了肾静脉血浆和肾脏中 PGI2 的产生，而不是 PGE2。I/R 明显降低了肾血流量，并增加了 O2 的产生、PGE2 的产生、两个烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚基 P47 和 Rac-1 的表达、细胞质细胞色素 C 的释放、促凋亡标志物 lamin 的表达、坏死、凋亡和自噬的病理表现以及受损肾脏中的血尿素氮和肌酐水平。Adv-COPI 保护远端和近端肾小管免受缺氧/复氧增强的氧化应激和自噬、凋亡和坏死性细胞死亡。Adv-COPI 通过恢复肾血流量、减少烟酰胺腺嘌呤二核苷酸磷酸氧化酶衍生和线粒体衍生的氧化应激以及坏死、凋亡和自噬，显著改善了肾功能。
Adv-COPI 增加的 PGI2 可保护肾脏免受 I/R 引起的氧化应激、坏死、凋亡和自噬。
