Agarwal A, Balla J, Alam J, Croatt A J, Nath K A
Department of Medicine, University of Minnesota Medical School, Minneapolis, USA.
Kidney Int. 1995 Oct;48(4):1298-307. doi: 10.1038/ki.1995.414.
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 flow 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.(ABSTRACT TRUNCATED AT 250 WORDS)
血红素的细胞含量受血红素加氧酶调节，血红素加氧酶是血红素降解中的限速酶。在血红素蛋白介导的肾损伤体内模型（急性肾衰竭的甘油模型）中，血红素加氧酶的诱导是一种保护反应。除了血红素外，多种形式的氧化应激也可诱导血红素加氧酶，但其功能意义目前尚不清楚。我们研究了在两种氧化剂诱导的中毒性肾病体内模型（即顺铂和庆大霉素肾病）中，血红素加氧酶是否被诱导以及这种诱导的功能意义；在这些模型中，肾毒性不像甘油模型那样依赖于向肾脏输送血红素蛋白。我们证明，单次注射顺铂（6毫克/千克静脉注射）后6小时和12小时，肾脏中血红素加氧酶mRNA和蛋白就开始被诱导。用血红素加氧酶的竞争性抑制剂锡原卟啉预处理，导致第3至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。顺铂注射后第2天对大鼠肾血流动力学的研究表明，用锡原卟啉处理的大鼠肾血流量降低、肾血管阻力增加、钠排泄分数增加。单独使用锡原卟啉对肾脏完好无损的大鼠的血清肌酐和肾血流动力学没有显著影响。我们证实锡原卟啉可阻止顺铂诱导的血红素加氧酶活性增加。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有关。（摘要截短至250字）
