INDUCTION OF HEME OXYGENASE IN TOXIC RENAL INJURY - A PROTECTIVE ROLE IN CISPLATIN NEPHROTOXICITY IN THE RAT
INDUCTION OF HEME OXYGENASE IN TOXIC RENAL INJURY - A PROTECTIVE ROLE IN CISPLATIN NEPHROTOXICITY IN THE RAT
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DOI：
10.1038/ki.1995.414
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发表时间：
1995-10-01
影响因子：
19.6
通讯作者：
NATH, KA
中科院分区：
文献类型：
--
作者：
AGARWAL, A;BALLA, J;NATH, KA
血红素加氧酶是血红素降解的限速酶，它调节细胞内血红素的含量。血红素加氧酶的诱导是血红素蛋白介导的肾损伤的体内模型（急性肾衰竭的甘油模型）中的保护性应答。除了血红素，血红素加氧酶是由不同形式的氧化应激，其功能意义目前尚不清楚。我们研究了血红素加氧酶是否被诱导，以及这种诱导的功能意义，在两个体内模型的氧化剂诱导的中毒性肾病，即顺铂和庆大霉素肾病;在这些模型中的肾毒性是不依赖于交付的血红素蛋白质的负担发生在甘油模型中的肾脏。我们证明诱导血红素加氧酶mRNA和蛋白质在肾脏早在6和12小时后，单剂量的顺铂（6毫克/公斤静脉注射）。用血红素加氧酶竞争性抑制剂锡原卟啉预处理，导致第3天至第5天血清肌酐值升高，第5天菊粉清除率降低;锡原卟啉还加剧了该模型中的肾损伤。顺铂治疗后第2天的肾血流动力学研究表明，用锡原卟啉治疗的大鼠肾血流速率降低，肾血管阻力增加，钠排泄分数增加。锡原卟啉单独对血清肌酐和肾脏血流动力学无显着影响与完整，无病肾大鼠。我们证实，锡原卟啉阻止顺铂诱导的血红素加氧酶活性的增加。顺铂诱导血红素加氧酶与肾脏血红素含量和铁蛋白含量增加相关。血红素加氧酶的诱导，通过mRNA和蛋白质含量测定，也发生在庆大霉素肾病，但低于顺铂肾病。血红素加氧酶的抑制并不影响庆大霉素肾病患者血清肌酐的连续测定，因此表明血红素加氧酶在氧化应激中诱导的功能意义存在异质性。我们的结论是，血红素加氧酶的诱导是一种保护性反应中毒性肾病，特别是顺铂肾病。铁蛋白含量也通过顺铂增加，并且通过螯合铁，可以在该模型中发挥有益作用。从血红素蛋白质释放的内源性血红素具有潜在毒性，并且可能导致顺铂肾毒性。
Cellular content of heme is regulated by heme oxygenase, the rate limiting enzyme in the degradation of heme. Induction of heme oxygenase is a protective response in an in vivo model of heme protein mediated renal injury, the glycerol model of acute renal failure. In addition to heme, heme oxygenase is induced by diverse forms of oxidative stress, the functional significance of which is currently unknown. We examined whether heme oxygenase is induced, and the functional significance of such induction, in two in vivo models of oxidant-induced toxic nephropathy, namely, cisplatin and gentamicin nephropathies; nephrotoxicity in these models is not dependent on the delivery of a burden of heme proteins to the kidney as occurs in the glycerol model. We demonstrate induction of heme oxygenase mRNA and protein in the kidney as early as 6 and 12 hours after a single dose of cisplatin (6 mg/kg i.v.). Pretreatment with tin protoporphyrin, a competitive inhibitor of heme oxygenase, led to higher serum creatinine values on days 3 through 5 and lower inulin clearances on day 5; tin protoporphyrin also exacerbated renal injury in this model. Renal hemodynamics studied at day 2 after cisplatin demonstrate reduced renal blood how rates, increased renal vascular resistance and increased fractional excretion of sodium in rats treated with tin protoporphyrin. Tin protoporphyrin alone had no significant effect on serum creatinine and renal hemodynamics in rats with intact, disease-free kidneys. We confirmed that tin protoporphyrin prevented the increase in heme oxygenase activity induced by cisplatin. Induction of heme oxygenase by cisplatin was associated with increased kidney heme content and ferritin content. Induction of heme oxygenase, as measured by mRNA and protein content, also occurred in gentamicin nephropathy, though less than that observed in cisplatin nephropathy. Inhibition of heme oxygenase did not influence sequential serum creatinine determinations in gentamicin nephropathy, thus indicating heterogeneity in the functional significance of induction of heme oxygenase in oxidative stress. We conclude that the induction of heme oxygenase is a protective response in toxic nephropathy, specifically, in cisplatin nephropathy. Ferritin content is also increased by cisplatin, and by sequestering iron, may subserve a beneficial role in this model, Endogenous heme, released from heme proteins, is potentially toxic and may contribute to cisplatin nephrotoxicity.