A prostacyclin analog prevents radiocontrast nephropathy via phosphorylation of cyclic AMP response element binding protein
A prostacyclin analog prevents radiocontrast nephropathy via phosphorylation of cyclic AMP response element binding protein
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DOI：
10.1016/s0002-9440(10)62352-8
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发表时间：
2005-05-01
影响因子：
6
通讯作者：
Oishi, R
中科院分区：
文献类型：
--
作者：
Yano, T;Itoh, Y;Oishi, R
我们以前报道过，放射性造影剂诱导半胱天冬酶依赖性细胞凋亡和cAMP类似物抑制培养的肾小管细胞的细胞损伤。在本研究中，确定了cAMP保护作用的细胞机制。碘佛醇，一种放射性造影剂，引起细胞损伤伴随着Bcl-2的减少，Bax的增加，和半胱天冬酶的激活LLC-PK 1细胞。双丁酰cAMP和前列环素类似物贝前列素均抑制碘佛醇诱导的细胞损伤和细胞事件。二丁酰cAMP增加Akt和CREB的磷酸化，这两者都被H89、渥曼青霉素和Akt抑制剂SH-6逆转。双丁酰cAMP的保护作用也被这些激酶抑制剂逆转。在显性阴性CREB转染细胞中，二丁酰cAMP不再阻止细胞损伤或抑制Bcl-2和Bax mRNA表达的变化。在单侧肾闭塞小鼠中，碘佛醇增加了N-乙酰-β-D-氨基葡萄糖苷酶的尿排泄，同时Bcl-2 mRNA降低，Bax mRNA增加，半胱天冬酶-3活化，并诱导肾小管和间质细胞凋亡。贝前列素完全逆转碘佛醇的这些体内作用。这些发现表明，内源性cAMP的升高通过激活A激酶/PI 3-激酶/Akt，随后CREB磷酸化和Bcl-2表达增强有效地预防放射造影剂肾病。
We reported previously that radiocontrast medium induces caspase-dependent apoptosis and that cAMP analogs inhibit cell injury in cultured renal tubular cells. in the present study, cellular mechanisms underlying the protective effects of cAMP were determined. Ioversol, a radiocontrast medium, caused cell injury accompanied by decreases in Bcl-2, increases in Bax, and caspase activation in LLC-PK1 cells. Both cell injury and cellular events induced by ioversol were inhibited by dibutyryl cAMP and the prostacyclin analog beraprost. Dibutyryl cAMP increased phosphorylation of Akt and CREB, both of which were reversed by H89, wortmannin and the Akt inhibitor SH-6. The protective effect of dibutyryl cAMP was also reversed by these kinase inhibitors. In dominant-negative CREBtransfected cells, dibutyryl cAMP no longer prevented cell injury or inhibited changes in mRNA expression of Bcl-2 and Bax. In mice with unilateral renal occlusion, ioversol increased urinary excretion of N-acetyl-beta-D-glucosaminidase with concomitant decreases in Bcl-2 mRNA, increases in Bax mRNA, activation of caspase-3, and induction of apoptosis in tubular and interstitial cells. Beraprost completely reversed these in vivo effects of ioversol. These findings suggest that elevation of endogenous cAMP effectively prevents radiocontrast nephropathy through activation of A kinase/PI 3-kinase/Akt followed by CREB phosphorylation and enhanced expression of Bcl-2.