Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inf lammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its pro ducts, we hypothesized that HO would be important for the regulation of blo od pressure and ischemic injury. We studied chronic renovascular hypertensi on in mice deficient in the inducible isoform of HO (HO-1) using a one kidn ey-one clip (1K1C) model of disease. Systolic blood pressure was not differ ent between wild-type (HO-1(+/+)), heterozygous (HO-1(+/-)), and homozygous null (HO-1(-/-)) mice at baseline. After 1K1C surgery, HO-1(+/+) mice deve loped 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 mmHg) 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, Hi stological 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 d ata suggest that chronic deficiency of HO-1 does not alter basal blood pres sure; however, in the 1K1C model an absence of HO-1 leads to more severe re novascular hypertension and cardiac hypertrophy. Moreover, renal artery cli pping leads to an acute increase in ischemic damage and death in the absenc e of HO-1.