Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis

Abstract

Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues’ AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease.

Graphical abstract

Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.

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Funding

The authors financial support for the current study from the Vice Chancellor for Research Affairs and Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences (Grant # 98-01-05-19529), Shanxi Government Scholarship for International Research Assistant (China National Natural Science Foundation; 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).

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VG, BK, OF, XS, and YC were involved in the data collection, data analysis, writing of the manuscript draft, and confirmation of the final manuscript. RH, HL, MM O, and AJ were involved in visualization of the data, writing the manuscript draft, and confirming the final manuscript. AJ, MMO, 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.

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Correspondence to Mohammad Mehdi Ommati 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 (#98-01-05-19529).

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Ghanbarinejad, V., Jamshidzadeh, A., Khalvati, B. et al. Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis. Naunyn-Schmiedeberg's Arch Pharmacol (2021). https://doi.org/10.1007/s00210-020-02041-7

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Keywords

  • Bile acids
  • Cirrhosis
  • Cytotoxicity
  • Mitochondrial dysfunction
  • Nephropathy
  • Oxidative stress