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. 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. 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