Oxidative and Nitrosative Stress in Chronic Cholestasis

doi:10.1016/B978-0-12-804274-8.00017-5

Liver Pathophysiology

Therapies and Antioxidants

2017, Pages 225-237

https://doi.org/10.1016/B978-0-12-804274-8.00017-5 Get rights and content

Abstract

Chronic cholestatic conditions are characterized by metabolic alterations in bile salts, lipids, and nutrients, and are associated to membrane lipid destruction and mitochondrial dysfunction. Primary biliary cholangitis, the most common chronic cholestatic condition in humans, is an autoimmune disease characterized by progressive intralobular bile duct destruction. Oxidative and nitrosative stress appear as underlying motors contributing to the ongoing biochemical and morphological changes of the liver. Abnormalities in both nitric oxide metabolism and in redox state of organosulfur (thiol) molecules occur already at early stages, suggesting that such events may have a fundamental pathogenic role in the disease development, and that may potentially be used as diagnostic markers of disease progression. Pharmacological interventions contrasting intra- and extracellular oxidative and nitrosative stress might restore morphological and functional changes. With this objective, ursodeoxycholic acid has been tested to protect against oxidative and nitrosative stress in the early stages of chronic cholestasis.

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Cited by (7)

Poly (ADP-Ribose) polymerase-1 (PARP-1) overactivity plays a pathogenic role in bile acids-induced nephrotoxicity in cholestatic rats
2020, Toxicology Letters
Citation Excerpt :
It has been well-documented that oxidative stress is a fundamental mechanism involved in the pathogenesis of CN (Bomzon et al., 1997; Heidari et al., 2019). Oxidative stress is closely related to inflammatory response, mitochondrial impairment, and tissue fibrosis (Grattagliano et al., 2017; Woolbright and Jaeschke, 2012). In the current study, the relationship between oxidative stress biomarkers, inflammatory response, tissue fibrosis, and PARP-1 expression and activity has been investigated in the renal tissue of cholestatic animals.
Cholestatic liver disease is a clinical complication with a wide range of etiologies. The liver is the primary organ influenced by cholestasis. Other organs, rather than the liver (e.g., kidneys), could also be affected by cholestatic liver disease. Cholestasis-induced renal injury is known as cholemic nephropathy (CN). Although the structural and functional alterations of the kidney in cholestasis have been well described, the cellular and molecular mechanisms of CN are not well understood. Some studies mentioned the role of oxidative stress and mitochondrial impairment in CN. Several cellular targets, including proteins, lipids, and DNA, could be affected by oxidative stress. Poly (ADP-Ribose) polymerase-1 (PARP-1) is an enzyme that its physiological activity plays a fundamental role in DNA repair. However, PARP-1 overexpression is associated with enhanced oxidative stress and cell death. The current study was designed to evaluate the role of PARP-1 activity in the pathogenesis of CN. Bile duct ligated (BDL) rats were treated with nicotinamide (NA) as a PARP-1 inhibitor. Kidney, urine, and plasma samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Serum and urine biomarkers of kidney injury, markers of oxidative stress and DNA damage, PARP-1 expression and activity in the kidney tissue, inflammatory response, renal fibrosis markers, and kidney histopathological alterations were assessed. Significant changes in the serum and urine biomarkers of kidney injury were evident in the BDL rats. Markers of oxidative stress were increased, and tissue ATP levels and antioxidant capacity were decreased in the kidney of cholestatic animals. A significant increase in PARP-1 expression and activity was evident in BDL rats (3, 7, 14, and 28 days after BDL). Moreover, inflammatory response (IL-1β and TNF-α expression; and myeloperoxidase activity), renal tissue histopathological alterations, and kidney fibrosis (α-SMA and TGF-β expression, as well as collagen deposition) were detected in cholestatic animals. It was found that the PARP-1 inhibitor, NA (50 and 100 mg/kg, i.p), significantly mitigated cholestasis-induced renal injury. The positive effects of NA were more significant at a lower dose and the early stage of CN. These data indicate a pathogenic role for PARP-1 overexpression in CN.
Agmatine alleviates hepatic and renal injury in a rat model of obstructive jaundice
2020, PharmaNutrition
Citation Excerpt :
Interestingly, Cecilia et al. also found a correlation between oxidative stress and the progression of jaundice-related renal dysfunction in humans [36]. The release of nitric oxide (NO) and nitrosative stress also seem to play an essential role in the pathogenesis of cholestasis-induced organ injury [85,86]. The protective effects of agmatine have been repeatedly mentioned in previous studies.
The cholestatic liver disease could develop in association with a wide range of etiologies. The liver is the most affected organ by cholestasis. It has also been found that the kidney is severely injured during cholestasis. Oxidative stress seems to play a fundamental role in the pathogenesis of cholestasis-induced hepatic and renal injury. The current study was designed to evaluate the effects of agmatine supplementation on hepatic and renal injury and its potential mechanisms of action.
Rats underwent bile duct ligation (BDL) surgery. BDL animals were treated with agmatine (5, 10, and 20 mg/kg, gavage) for seven consecutive days.
Significant reactive oxygen species formation, lipid peroxidation, increased oxidized glutathione level, decreased tissue antioxidant capacity and depleted reduced glutathione (GSH) were detected in cholestatic animals. Moreover, mitochondrial indices, including ATP level, membrane potential, lipid peroxidation, and swelling, were deteriorated in both liver and kidney of cholestatic rats. Liver fibrosis and renal tissue histopathological changes were also evident in BDL rats. It was found that agmatine supplementation significantly alleviated cholestasis-induced hepatic and renal injury.
The mechanism of action of agmatine could be related to its antioxidant properties and the positive effects of this amine on mitochondrial indices.
Ovothiol-a isolated from sea urchin eggs suppress oxidative stress, inflammation, and dyslipidemia resulted in restoration of liver activity in cholestatic rats
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Cellular and mitochondrial taurine depletion in bile duct ligated rats: a justification for taurine supplementation in cholestasis/cirrhosis
2022, Clinical and Experimental Hepatology
The activation of nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling blunts cholestasis-induced liver and kidney injury
2021, Toxicology Research
Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis
2021, Naunyn-Schmiedeberg's Archives of Pharmacology

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Chapter 17 - Oxidative and Nitrosative Stress in Chronic Cholestasis

Abstract