Silymarin mitigates bile duct obstruction-induced cholemic nephropathy

Abstract

Bile duct obstruction or cholestasis can occur by several diseases or xenobiotics. Cholestasis and the accumulation of the bile constituents in the liver primarily damage this organ. On the other hand, extrahepatic organs are also affected by cholestasis. The kidney is the most affected tissue during cholestatic liver injury. Cholestasis-associated renal injury is known as cholemic nephropathy (CN). Several lines of evidence specify the involvement of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to assess the role of silymarin as a potent antioxidant on CN-induced oxidative stress and mitochondrial dysfunction in the kidney. Bile duct ligated (BDL) rats were treated with silymarin (10 and 100 mg/kg, oral) for seven consecutive days. A significant increase in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and oxidized glutathione (GSSG) levels were evident in the kidney of BDL animals. Moreover, reduced glutathione (GSH) content and total antioxidant capacity were significantly decreased in the kidney of cholestatic rats. Mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depleted ATP stores were detected in the kidney mitochondria isolated from BDL animals. Kidney histopathological alterations, as well as serum and urine levels of renal injury biomarkers, were also significantly different in the BDL group. It was found that silymarin treatment significantly ameliorated CN-induced renal injury. The antioxidant effects of silymarin and its positive impact on mitochondrial indices seem to play a significant role in its renoprotective effects during cholestasis.

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Data availability

All data and materials as well as software (GraphPad Prism® 8 and ImageJ™) support the published claims in this manuscript and comply with field standards. Manuscript data will be available on demand.

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Acknowledgments

The authors acknowledge the advice of Professor Akram Jamshidzadeh in this research.

Funding

This investigation was financially supported by the Vice-Chancellor of Research Affairs of Shiraz University of Medical Sciences (Grant: 97-01-36-16746, provided by Dr. R. Heidari) and Shanxi Government Scholarship for International Research Assistant (National Natural Science Foundation of China (CN); Grant No. 2018YJ33; provided by Dr. M. Mehdi Ommati), and outstanding doctors volunteering to work in Shanxi Province (No. K271999031; by Dr. M. Mehdi Ommati), Shanxi Province, China.

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MMO, OF, and EG were involved in the data collection, data analysis, writing of the manuscript draft, and confirmation of the final manuscript. RH, NA, and HN were involved in visualization of the data, writing the manuscript draft, and proof of the final document. MMO, NA, HN, and RH were also involved in project supervision and study conceptualization. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Hossein Niknahad or Reza Heidari.

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Experimental animals, rats, were used according to the guidelines approved by the ethics committee of Shiraz University of Medical Sciences, Shiraz, Iran (#97-01-36-16746).

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The authors declare that they have no competing interests.

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Ommati, M.M., Farshad, O., Azarpira, N. et al. Silymarin mitigates bile duct obstruction-induced cholemic nephropathy. Naunyn-Schmiedeberg's Arch Pharmacol (2021). https://doi.org/10.1007/s00210-020-02040-8

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Keywords

  • Bile acids
  • Cholestasis
  • Cirrhosis
  • Mitochondria
  • Nephropathy
  • Oxidative stress
  • Renal failure