title: Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration.
abstract: The phenomenon known as renal "ischemic preconditioning," whereby an initial ischemic insult induces resistance against subsequent kidney damage, has been well established in the experimental literature. However, a clinically applicable way to safely recapitulate this state has not been defined. We hypothesized that a unique combination of agents (nitrited myoglobin [N-Mgb] + tin protoporphyrin [SnPP]) can achieve these ends safely and synergistically, increasing cytoprotective proteins (eg, heme oxygenase 1 [HO-1], interleukin 10 [IL-10], and haptoglobin) in kidney cells. To test this hypothesis, CD-1 mice received 1 mg of N-Mgb and 1 μmol of SnPP, either alone or in combination. Renal cortical HO-1, haptoglobin, and IL-10 gene expressions (messenger RNA [mRNA], protein levels) were determined 4 and 18 hours later. Cytoresistance to 3 forms of acute kidney injury (AKI; glycerol-induced rhabdomyolysis, maleate nephrotoxicity, and postischemic AKI progression to chronic kidney disease [CKD]) was assessed. To ascertain whether cytoresistance might emerge in extrarenal organs, hepatic HO-1, IL-10, and haptoglobin levels were also measured, and resistance to 25 minutes of hepatic ischemia-reperfusion injury and hepatotoxicity (intraperitoneal glycerol injection) was sought. N-Mgb + SnPP induced additive or synergistic increases in renal HO-1, haptoglobin, and IL-10 mRNA and protein levels (up to 20-fold) without inducing any apparent renal or extrarenal damage. After 18 hours of post-treatment, marked or complete protection against glycerol-induced AKI, maleate-induced AKI, and postischemic AKI progression to CKD had emerged. Combined N-Mgb + SnPP was more protective than either agent alone (assessed in glycerol model). N-Mgb + SnPP also upregulated cytoprotective pathways in liver and induced marked protection against both hepatic ischemia-reperfusion and toxic liver damage. In conclusion, we posit that "preconditioning" with combined administration of N-Mgb + SnPP represents a promising approach for protecting against diverse forms of renal and nonrenal (hepatic) forms of tissue damage.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Wash; Department of Medicine, University of Washington, Seattle, Wash. Electronic address: dzager@fhcrc.org.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000293:injuries* / Q000503:physiopathology; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage*; D051379:Mice; D009211:Myoglobin / Q000008:administration & dosage* / Q000737:chemistry; D009573:Nitrites / Q000737:chemistry*; D011524:Protoporphyrins / Q000008:administration & dosage*
chemical_list: D008665:Metalloporphyrins; D009211:Myoglobin; D009573:Nitrites; D011524:Protoporphyrins; C032628:tin protoporphyrin IX