The role of Ca²⁺ signalling and InsP3R in the pathogenesis of intrahepatic cholestasis of pregnancy

Abstract

Background

In order to contribute new insights for future prevention and treatment of intrahepatic cholestasis of pregnancy (ICP), and to promote positive pregnancy outcomes, we evaluated serum Ca²⁺ levels and inositol 1,4,5-trisphosphate receptor (InsP3R) expression in the liver tissue of a rat ICP model.

Methods

After establishing the model by injection of oestradiol benzoate and progesterone into pregnant rats, animals were divided into normal control (n = 5) and ICP model groups (n = 5). The expression of InsP3R protein in the liver, and serum levels of Ca²⁺, glycocholic acid and bile acid were detected.

Results

InsP3R mRNA and protein were significantly lower in the ICP model group compared to the normal group, as determined by qPCR and immunohistochemistry, respectively. Serum enzyme-linked immunosorbent assay results revealed significantly higher levels of glycocholic acid and bile acid in the ICP model group compared to the normal group, while Ca²⁺ levels were significantly lower. The levers of Ca²⁺ were significantly and negatively correlated with the levels of glycocholic acid. The observed decrease in Ca²⁺ was associated with an increase in total bile acids, but there was no significant correlation.

Conclusions

Our results revealed that the expression of InsP3R and serum Ca²⁺ levels was significantly decreased in the liver tissue of ICP model rats. Additionally, Ca²⁺ levels were found to be negatively correlated with the level of glycocholic acid.

PLAIN LANGUAGE SUMMARY

This study investigated the relationship between serum Ca²⁺ levels, inositol 1,4,5-trisphosphate receptor (InsP3R) expression and intrahepatic cholestasis of pregnancy (ICP) in a rat model. The results indicated a significant decrease in InsP3R expression and Ca²⁺ in the disease group compared to the control group, alongside elevated levels of glycocholic acid and bile acid. The levels of Ca²⁺ exhibited a negative correlation with the levels of glycocholic acid. These findings indicated that the decrease of InsP3R expression and Ca²⁺ levels may be related to the pathogenesis of ICP. The study provides further insight into the treatment of this disease.

Keywords:

• Intrahepatic cholestasis of pregnancy
• InsP3R
• calcium ion

Acknowledgements

We thank Liwen Bianji (Edanz) (www.liwenbianji.cn/) for basic language editing of a draft of this manuscript.

Author contributions

D.P. and M.J. made substantial contributions to acquisition, analysis and interpretation of the data, and wrote the first draft of the manuscript; M.J., G.T., J.S., Z.S., R.C. and D.W. made substantial contributions to acquisition of data. D.P. and D.W. contributed to experimental conception and design, and analysis and interpretation of data, and drafted the manuscript and revised it critically. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All generated raw data and/or analysed data from the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by the Medical and Health Science and Technology Projects of Zhejiang Province under Grant [2022KY1388].