Mishima Kazuto, Baba Anri, Matsuo Misaki, Itoh Yoshinori, Oishi Ryozo
Department of Pharmacy, Kyushu University Hospital 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Free Radic Biol Med. 2006 May 1;40(9):1564-77. doi: 10.1016/j.freeradbiomed.2005.12.025. Epub 2006 Jan 18.
We reported earlier that reactive oxygen species are implicated in necrotic injury induced by a transient exposure of cultured renal tubular cells to a high concentration of cisplatin but not in apoptosis occurring after continuous exposure to a low concentration of cisplatin. We report here the protective effect of cyclic AMP against cisplatin-induced necrosis in cultured renal tubular cells as well as cisplatin-induced acute renal failure in rats. Several pharmacological agents that stimulate cyclic AMP signaling, including the nonhydrolyzable cyclic AMP analogue dibutyryl cyclic AMP, forskolin, 3-isobutyl-1-methylxanthine, and a prostacyclin analogue, beraprost, prevented cisplatin-induced cell injury in a protein kinase A-dependent manner. Cisplatin enhanced lipid peroxidation, decreased CuZn superoxide dismutase (SOD) while enhancing MnSOD activity, and increased cellular tumor necrosis factor-alpha (TNF-alpha) content. The elevation of TNF-alpha content and cell injury induced by cisplatin were attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors including SB203580 and PD169316. Indeed, cisplatin increased the number of phosphorylated p38 MAPK-like immunoreactive cells. These intracellular events were all reversed by antioxidants such as N-acetylcysteine (NAC) and glutathione or cyclic AMP analogues. The in vivo acute renal injury after cisplatin injection was associated with the elevation of renal TNF-alpha content. The cisplatin-induced renal injury and the increase in TNF-alpha content were reversed by NAC or beraprost. These findings suggest that cyclic AMP protects renal tubular cells against cisplatin-induced oxidative injury by obliterating reactive oxygen species and subsequent inhibition of TNF-alpha synthesis through blockade of p38 MAPK activation.
我们之前报道过，活性氧参与了培养的肾小管细胞短暂暴露于高浓度顺铂所诱导的坏死性损伤，但不参与连续暴露于低浓度顺铂后发生的凋亡。我们在此报告环磷酸腺苷（cAMP）对培养的肾小管细胞中顺铂诱导的坏死以及对大鼠顺铂诱导的急性肾衰竭的保护作用。几种刺激cAMP信号传导的药物制剂，包括不可水解的cAMP类似物二丁酰cAMP、福斯可林、3 -异丁基-1 -甲基黄嘌呤以及一种前列环素类似物贝拉普罗斯，以蛋白激酶A依赖的方式预防了顺铂诱导的细胞损伤。顺铂增强了脂质过氧化作用，降低了铜锌超氧化物歧化酶（SOD），同时增强了锰超氧化物歧化酶活性，并增加了细胞肿瘤坏死因子-α（TNF-α）含量。包括SB203580和PD169316在内的p38丝裂原活化蛋白激酶（MAPK）抑制剂减轻了顺铂诱导的TNF-α含量升高和细胞损伤。实际上，顺铂增加了磷酸化p38 MAPK样免疫反应性细胞的数量。这些细胞内事件都被抗氧化剂如N-乙酰半胱氨酸（NAC）、谷胱甘肽或cAMP类似物逆转。顺铂注射后的体内急性肾损伤与肾TNF-α含量升高有关。NAC或贝拉普罗斯逆转了顺铂诱导的肾损伤和TNF-α含量增加。这些发现表明，cAMP通过消除活性氧并随后通过阻断p38 MAPK活化抑制TNF-α合成，从而保护肾小管细胞免受顺铂诱导的氧化损伤。
