Decreased renal heme oxygenase-1 expression contributes to decreased renal function during cirrhosis.
Heme oxygenase (HO) is the rate-limiting enzyme in the degradation of heme, catalyzing the oxidative cleavage of heme molecules to biliverdin, carbon monoxide, and iron. The present study was designed to investigate the role of HO-1 in the pathogenesis of renal dysfunction during cirrhosis. Biliary cirrhosis was induced in rats by common bile duct ligation (CBDL). Animals were studied 2 and 5 wk after surgery. In kidney from CBDL rats, HO-1 protein expression increased slightly at 2 wk but was abolished at 5 wk. In addition, we confirmed histologically that HO-1 expression was suppressed in renal tubules and interlobular arterioles in 5-wk-old CBDL rats. Conversely, HO-1 expression in liver was strongly increased. Consistent with the development of cirrhosis and renal dysfunction mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal blood flow (RBF) were decreased in CBDL rats compared with sham-operated controls. In sham rats, treatment with the selective HO inhibitor zinc protoporphyrin markedly decreased GFR and RBF to values similar to those measured in CBDL rats without decreasing MAP. In conclusion, decreased renal HO-1 expression contributes to deteriorated renal function and hemodynamics during cirrhosis. This finding provides a novel mechanism for the pathophysiology of renal dysfunction during cirrhosis.
Miyazono
Motoaki
M
Cardiovascular-Pulmonary Research Laboratory and Departments of Medicine and Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Garat
Chrystelle
C
Morris
Kenneth G
KG
Carter
Ethan P
EP
D000818:Animals; D001835:Body Weight; D002248:Carbon Monoxide / Q000378:metabolism; D005919:Glomerular Filtration Rate; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000378:metabolism; D051547:Heme Oxygenase-1; D007150:Immunohistochemistry; D007668:Kidney / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation
D009569:Nitric Oxide; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2