| The significant renal complications frequently occur during liver cirrhosis, such as water imbalance, sodium retention, and activation of intrarenal hormones. The causes of renal function impairment during liver cirrhosis are still unclear. The disturbance of renal hemodynamics caused by severe liver diseases may play an important role. The characteristics of renal hemodynamics during hepatic cirrhosis were as following: constriction of intrarenal blood vessels, redistribution of renal blood, diffluence of blood flowed from renal cortex to medulla, cortex ischemia, constriction of afferent glomerular arteriole and glomerular filtration rate (GFR) decreased. Despite elevated levels of vasodilatation factors in the systemic circulation for the reason that inactivation reduced or overproduction, activities of vasoconstriction factors were to gain advantage locally in the kidney. Consistent with the development of the liver cirrhosis, renal vessel constriction intensified, the resistance of renal vessel increased. These may lead to a decrease of GFR and renal blood flow, resulting in proceeding uropenia, anuria, the concentrations of creatinine and urea nitrogen were increased, at last developing into hepatorenal syndrome. Recent studies found that carbon monoxide (CO), like nitric oxide (NO), is a gas messenger. Besides participating in the convection of signal in the central nervous system, it also plays an important role in vascular tone regulation. We therefore aimed to investigate whether CO may also play a pathogenic role in the regulation of renal vessels of liver cirrhotic rats. Heme oxygenase(HO)is a heme oxidizing enzyme,which can catalyze heme molecules and generate biliverdin, carbon monoxide and free iron.Someone has recently reported that endothelial nitric oxide synthase (eNOS) expression in the lungs and plasma nitric oxide (NO) metabolites levels are elevated after common bile duct ligation (CBDL) but that the acute inhibition of NO only partially reversed the blunted hypoxic pulmonary vasoconstriction. So there is a possibility that the elevated NO during cirrhosis was acting not only as a vasodilator, but also as a regulator of gene expression of other vasoactive mediators such as heme oxygenases-1(HO-1). HO are the rate-limiting enzymes in heme degradation, catalyzing the breakdown of heme to equimolar quantities biliverdin, carbon monoxide (CO), and ferrous iron.Studies on apoptosis were made rapidly and deeply development in life science field since Kerr first put forward the concept of apoptosos in 1972. The term"apoptosis"refers to a morphological phenomenon. The characteristics of an apoptotic cell include chromatin condensation, nuclear fragmentation and cell shrinkage. Eventually, the cell breaks into small membrane-surrounded fragments or apoptotic bodies. As a gene-directed process, apoptosis is modulated by the expression of a number of regulatory genes, such as p53, c-myc and Bcl-2 family. Bcl-2 and Bax are two members of the Bcl-2 gene family. Bcl-2 is known to protect against apoptosis triggered by a wide range of factors. However, the inhibitory effect of Bcl-2 on apoptosis is determined by the interaction with Bax, with a degree of homology to Bcl-2. When Bcl-2 is in excess, cells are protected from apoptosis, and when Bax is in excess and homodimers of Bax dominate, cells are susceptible to apoptosis. So it appears that the relative ratio of Bax and Bcl-2 determines the fate of cell.Objective: Using a rat model of liver cirrhosis induced by common bile duct ligation (CBDL), we observed renal pathological changes, examined the expression and location of HO-1 in the renal tissues, detected the serum concentration of malonaldehyde (MDA), the renal apoptosis and expressions of Bcl-2 and Bax, so as to investigate the renal pathologic changes and the mechanisms of renal dysfunction following the hepatic cirrhosis progression.Methods: Hepatic cirrhosis rats were induced by CBDL. Rats were studied at 2 wk and 5 wk after CBDL or sham operation. The renal tissue changes of CBDL rat were examined by pathology and electron microscope observation. The expression of HO-1 in the kidney was examined by immunohistochemical staining. The 24 hour urine and serum of rats were used for determining the creatinine clearance rat (Ccr) and malonaldehyde (MDA) by spectrophotometric method. The renal apoptotic index was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelin (TUNEL). Expressions of Bcl-2 and Bax were examined by immunohistochemistry.Results: Hepatic histological examinations: the macroscopic appearance of the liver showed the features of hepatic fibrosis at 2wk and biliary cirrhosis at 5wk after CBDL. The creatinine clearance rates were significantly decreased in group 2wk and 5wk rats. Renal pathological changes staining by HE shown that there were desquamate and necrosis of renal tubule epidermis in group week 5. Irregular thickening of glomerular basement membrane, mesangial expansion and fusion of foot processes were observed at week 5 by electron microscope. Immunohistochemical analysis: It was found that in the kidney of the cirrhotic rat, the numbers of HO-1 positive cells as well as intensity per cell were decreased. Expressions of HO-1 protein (positive areas percent) in sham operation, 2wk and 5wk CBDL rats were 53.04±12.79, 60.47±1.78 and 12.90±3.90 and 5wk singnidicangly decreased with 2wk or sham .However, there was no statistical difference of HO-1 protein between the sham operation and 2 wk rates (P=0.122). MDA in sham operationg, 2wk and 5wk CBDL rats were 0.79±0.37, 2.32±0.85 and 4.07±0.51, and significantly increased gradually step by step . (F=71.66, P=0.00). The apoptotic renal cells were piled up in renal tissue, which caryotheca became thicken. Its chromoplasm was pyknosiser or became pieces of mass. Apoptosis rates (positive areas percent) in sham operation, 2wk and 5wk CBDL rats were 11.43±2.77, 24.08±2.59 and 68.36±8.71, and there were significant differences among the three groups (F=297.00, P=0.00), meanwhile the apoptosis rate significantly increased gradually Corresponding gray scales of Bcl-2 and Bax in sham operation, 2wk CBDL, 5wk CBDL rats were (1.36±0.19 vs 1.23±0.15), (1.08±0.09 vs 1.50±0.19) and (0.75±0.13 vs 1.80±0.10), so the Bcl-2 decreased and Bax increased gradually. There was positive correlation between MDA and apoptosis, i.e. sham operation group r=0.9410 (P<0.05), 2wk group r=0.9113 (P<0.05) and 5wk group r= 0.8851 (P<0.01).Conclusion: The results of this study showed that①There was the pathologic changes in the kidney of the rats with liver cirrhosis induced by CBDL, and the renal pathological damages deteriorated following by the liver cirrhosis progression.②Expression of HO-1 protein decreased with hepatic pathologic tissue aggravation, so the abnormal HO expression in the kidney of CBDL cirrhotic rats might play an important role in the development of renal dysfunction during cirrhosis.③Apoptosis was one of factors inducing renal dysfunction in CBDL cirrhosis. Both promoting apoptosis gene Bax was overexpression and inhibiting apoptosis gene Bcl-2 hypoexpression were play an important role in the renal damages of CBDL cirrhosis, and the oxidative stress and free radical were also the key factor in this process. |
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