title: Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice.
abstract: Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice developed hypertension (140+/-2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0+/-0.2 mg/g) compared with sham-operated HO-1(+/+) mice (108+/-5 mm Hg and 4.1+/-0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164+/-2 mm Hg) and cardiac hypertrophy (6.9+/-0.6 mg/g) in HO-1(-/-) mice. HO-1(-/-) mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1(+/+) (25%) and HO-1(+/-) (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1(-/-) mice compared with HO-1(+/-) mice. Histological analysis of kidneys from 1K1C HO-1(-/-) mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1(-/-) and 1K1C HO-1(+/-) mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1.
authors.affiliation: Program of Developmental Cardiovascular Biology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: P
authors.initials: P
authors.lastname: Wiesel
authors.forename: A P
authors.initials: AP
authors.lastname: Patel
authors.forename: I M
authors.initials: IM
authors.lastname: Carvajal
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Pellacani
authors.forename: K
authors.initials: K
authors.lastname: Maemura
authors.forename: N
authors.initials: N
authors.lastname: DiFonzo
authors.forename: H G
authors.initials: HG
authors.lastname: Rennke
authors.forename: M D
authors.initials: MD
authors.lastname: Layne
authors.forename: S F
authors.initials: SF
authors.lastname: Yet
authors.forename: M E
authors.initials: ME
authors.lastname: Lee
authors.forename: M A
authors.initials: MA
authors.lastname: Perrella
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000150:complications / Q000473:pathology*; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D006579:Heterozygote; D006720:Homozygote; D006978:Hypertension, Renovascular / Q000097:blood / Q000150:complications / Q000235:genetics*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A; D012078:Renal Artery Obstruction / Q000150:complications; D012720:Severity of Illness Index; D015996:Survival Rate
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008565:Membrane Proteins; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D003404:Creatinine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse