Vitamin D₃ protects against prednisolone-induced liver injury associated with the impairment of the hepatic NF-κB/iNOS/NO pathway

Abstract

The study was carried out to define whether prednisolone-induced damage to hepatic cells is accompanied by excessive nitric oxide (NO) levels associated with nuclear factor kappa B (NF-κB)/inducible NO synthase (iNOS) activation and evaluate the efficacy of the treatment with vitamin D. Histopathological examination, activities of liver transaminases (alanine aminotransferase and aspartate aminotransferase), and cell death assays consistently showed that prednisolone (5 mg/kg body weight, 30 days) induces chronic liver injury in female Wistar rats. Specifically, increased hepatocellular necrosis and caspase-3-dependent apoptosis were observed. Prednisolone enhanced iNOS protein expression, NO generation, and tyrosine nitration in liver cells. Despite unchanged hepatic level of the NF-κB/p65 protein, prednisolone increased inhibitory κB-α (IκB-α) degradation, nuclear translocation, and phosphorylation of NF-κB/p65 at Ser311, indicating that NF-κB activation can be involved in the induction of iNOS/NO. All changes were associated with a 2.9-fold decrease in the serum content of 25-hydroxyvitamin D and significant reduction of hepatic vitamin D receptor (VDR) expression that points reliably to vitamin D deficiency and failures in VDR signaling. Vitamin D co-administration (100 IU/rat, 30 days) prevented glucocorticoid-evoked abnormalities in hepatic tissue. In conclusion, prednisolone-induced liver disturbances were associated with the impairment of NF-κB/iNOS/NO responses that can be ameliorated by vitamin D treatment through VDR-mediated mechanisms.

Vitamin D Protects Against Alcohol‐Induced Liver Cell Injury Within an NRF2–ALDH2 Feedback Loop

“…VD was regarded as a typical vitamin regulating calcium and phosphorus homeostasis previously . Recently VD is discovered as a highly versatile molecule with emerging roles in immunity, cancer, fatty liver disease, and ALD . A large body of clinical evidence has demonstrated the prevalence and risks of VD deficiency in various chronic diseases.…”

“…[20] Recently VD is discovered as a highly versatile molecule with emerging roles in immunity, cancer, fatty liver disease, and ALD. [21,22,28] A large body of clinical evidence has demonstrated the prevalence and risks of VD deficiency in various chronic diseases. Additionally, studies has documented that VD treatment could activate NRF2 signaling pathway in those related diseases.…”

“…Traditionally, VD is regarded as a typical vitamin modulating bone development by regulating calcium and phosphorus homeostasis . Now, VD is discovered as a highly versatile molecule with emerging roles in numbers of diseases . VD ameliorates nonalcoholic fatty liver disease by repressing oxidative stress and inflammation in an NRF2‐dependent manner .…”

“…[20] Now, VD is discovered as a highly versatile molecule with emerging roles in numbers of diseases. [21,22] VD ameliorates nonalcoholic fatty liver disease by repressing oxidative stress and inflammation in an NRF2-dependent manner. [23] Therefore, this study was to identify the protective mechanisms of VD in alcohol-induced cells injury.…”

Vitamin D protects against particles‐caused lung injury through induction of autophagy in an Nrf2‐dependent manner

“…Traditionally, vitamin D (VD) was regarded as a typical vitamin modulating bone development and regulating calcium and phosphorus homeostasis . Recently, VD is discovered as a highly versatile molecule with emerging roles in immunity, cancer, infectious diseases, toxins induced‐inflammation, and fibrosis . A large body of clinical evidence has demonstrated the prevalence and risks of VD deficiency in various chronic disease and toxins induced tissue damage .…”