title: Age sensitizes the kidney to heme protein-induced acute kidney injury.
abstract: Age increases the risk for ischemic acute kidney injury (AKI). We questioned whether a similar age-dependent injury occurs following exposure to hemoglobin, a known nephrotoxin. Old mice (~16 mo old), but not young mice (~6 mo old), when administered hemoglobin, exhibited marked elevation in blood urea nitrogen (BUN) and serum creatinine, and acute tubular necrosis with prominent tubular cast formation. The aged kidney exhibited induction of heme oxygenase-1 (HO-1) and other genes/proteins that may protect against heme-mediated renal injury, including ferritin, ferroportin, haptoglobin, and hemopexin. Old mice did not evince induction of HO-2 mRNA by hemoglobin, whereas a modest induction of HO-2 mRNA was observed in young mice. To determine the functional significance of HO-2 in heme protein-induced AKI, we administered hemoglobin to relatively young HO-2(+/+) and HO-2(-/-) mice: HO-2(-/-) mice, compared with HO-2(+/+) mice, exhibited greater renal dysfunction and histologic injury when administered hemoglobin. In addition to failing to elicit a protective system such as HO-2 in response to hemoglobin, old mice exhibited an exaggerated maladaptive response typified by markedly greater induction of the nephrotoxic cytokine IL-6 (130-fold increase vs. 10-fold increase in mRNA in young mice). We conclude that aged mice, unlike relatively younger mice, are exquisitely sensitive to the nephrotoxicity of hemoglobin, an effect attended by a failure to induce HO-2 mRNA and a fulminant upregulation of IL-6. Age thus markedly augments the sensitivity of the kidney to heme proteins, and HO-2 confers resistance to such insults.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Guggenheim 542, 200 First St., SW, Rochester, MN 55905, USA. nath.karl@mayo.edu
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000375:Aging / Q000502:physiology*; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006420:Hemeproteins / Q000009:adverse effects* / Q000378:metabolism; D006454:Hemoglobins / Q000009:adverse effects* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D006420:Hemeproteins; D006454:Hemoglobins; D015850:Interleukin-6; D012333:RNA, Messenger; D003404:Creatinine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2