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Decreased renal heme oxygenase-1 expression contributes to decreased renal function during cirrhosis
Motoaki Miyazono1, Chrystelle Garat, Kenneth G Morris
1Cardiovascular-Pulmonary Research Laboratory and Departments of Medicine and Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Insights
Decreased renal heme oxygenase-1 (HO-1) expression contributes to kidney dysfunction in cirrhosis. Suppressed HO-1 in kidneys of cirrhotic rats worsened renal hemodynamics, highlighting a novel mechanism in disease progression.
Area of Science:
- Biochemistry
- Nephrology
- Pathophysiology
Background:
- Heme oxygenase (HO) is key in heme degradation.
- Heme oxygenase-1 (HO-1) plays a role in cellular protection.
- Cirrhosis is associated with renal dysfunction.
Purpose of the Study:
- To investigate the role of HO-1 in renal dysfunction during cirrhosis.
- To examine HO-1 expression in the kidneys of rats with biliary cirrhosis.
Main Methods:
- Biliary cirrhosis induced in rats via common bile duct ligation (CBDL).
- HO-1 protein expression analyzed in kidneys and liver at 2 and 5 weeks post-surgery.
- Renal function assessed by mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal blood flow (RBF).
Main Results:
- Renal HO-1 expression was suppressed in 5-week CBDL rats, while liver HO-1 increased.
- CBDL rats showed decreased MAP, GFR, and RBF compared to controls.
- Inhibition of HO-1 in sham rats mimicked the renal dysfunction observed in CBDL rats.
Conclusions:
- Reduced renal HO-1 expression is a significant factor in the renal dysfunction and hemodynamic changes seen in cirrhosis.
- This study identifies a novel mechanism contributing to kidney impairment in cirrhotic conditions.
Abstract:
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.