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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References
Aniort J, Poyet A, Kemeny J-L, Philipponnet C, Heng A-E (2017) Bile cast nephropathy caused by obstructive cholestasis. Am J Kidney Dis 69:143–146. https://doi.org/10.1053/j.ajkd.2016.08.023
Arduini A, Serviddio G, Tormos AM, Monsalve M, Sastre J (2012) Mitochondrial dysfunction in cholestatic liver diseases. Front Biosci 4:2233–2252. https://doi.org/10.2741/539
Bano D, Prehn JHM (2018) Apoptosis-inducing factor (AIF) in physiology and disease: the tale of a repented natural born killer. EBioMedicine 30:29–37. https://doi.org/10.1016/j.ebiom.2018.03.016
Bomzon A, Holt S, Moore K (1997) Bile acids, oxidative stress, and renal function in biliary obstruction. Semin Nephrol 17:549–562
Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu S-S (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Phys Cell Phys 287:C817–C833. https://doi.org/10.1152/ajpcell.00139.2004
Cao G, Xing J, Xiao X, Liou AKF, Gao Y, Yin X-M, Clark RSB, Graham SH, Chen J (2007) Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci 27:9278–9293. https://doi.org/10.1523/JNEUROSCI.2826-07.2007
Carey EJ, Lindor KD (2014) Cholestatic liver disease. Springer, New York
Chang K-A, Lin IC, Sheen J-M, Chen Y-C, Chen C-C, Tain Y-L, Hsieh C-S, Huang L-T (2013) Sex differences of oxidative stress to cholestatic liver and kidney injury in young rats. Pediatr Neonatol 54:95–101. https://doi.org/10.1016/j.pedneo.2012.11.008
Copple BL, Jaeschke H, Klaassen CD (2010) Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis 30:195–204. https://doi.org/10.1055/s-0030-1253228
El Golli-Bennour E, Bacha H (2011) Hsp70 expression as biomarkers of oxidative stress: mycotoxins’ exploration. Toxicology 287:1–7. https://doi.org/10.1016/j.tox.2011.06.002
Elguindy MM, Nakamaru-Ogiso E (2015) Apoptosis-inducing factor (AIF) and its family member protein, AMID, are rotenone-sensitive NADH:ubiquinone oxidoreductases (NDH-2). J Biol Chem 290:20815–20826. https://doi.org/10.1074/jbc.M115.641498
Fayzullina S, Martin LJ (2014) Detection and analysis of DNA damage in mouse skeletal muscle in situ using the TUNEL method. J Vis Exp. https://doi.org/10.3791/52211
Fickert P, Krones E, Pollheimer MJ, Thueringer A, Moustafa T, Silbert D, Halilbasic E, Yang M, Jaeschke H, Stokman G (2013) Bile acids trigger cholemic nephropathy in common bile-duct–ligated mice. J Hepatol 58:2056–2069. https://doi.org/10.1002/hep.26599
Finsterer J, Scorza F (2017) Renal manifestations of primary mitochondrial disorders. Biomedical Reports 6:487–494. https://doi.org/10.3892/br.2017.892
Grattagliano I, Oliveira PJ, Vergani L, Portincasa P (2017) Chapter 17 - oxidative and nitrosative stress in chronic cholestasis. In: Muriel P (ed) Liver pathophysiology. Academic Press, Boston, pp 225–237
Heidari R (2019) The footprints of mitochondrial impairment and cellular energy crisis in the pathogenesis of xenobiotics-induced nephrotoxicity, serum electrolytes imbalance, and Fanconi’s syndrome: a comprehensive review. Toxicology 423:1–31. https://doi.org/10.1016/j.tox.2019.05.002
Heidari R, Behnamrad S, Khodami Z, Ommati MM, Azarpira N, Vazin A (2019) The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress. Biomed Pharmacother 109:103–111. https://doi.org/10.1016/j.biopha.2018.10.093
Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Esfandiari A, Azarpira N, Niknahad H (2018a) Dithiothreitol supplementation mitigates hepatic and renal injury in bile duct ligated mice: potential application in the treatment of cholestasis-associated complications. Biomed Pharmacother 99:1022–1032. https://doi.org/10.1016/j.biopha.2018.01.018
Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Ommati MM, Abdoli N, Aghaei F, Esfandiari A, Azarpira N, Niknahad H (2018b) Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice. Biomed Pharmacother 97:1086–1095. https://doi.org/10.1016/j.biopha.2017.10.166
Heidari R, Niknahad H (2019) The role and study of mitochondrial impairment and oxidative stress in cholestasis. In: Vinken M (ed) Experimental cholestasis research. Springer New York, New York, NY, pp 117–132
Holt S, Marley R, Fernando B, Harry D, Anand R, Goodier D, Moore K (1999) Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor. Kidney Int 55:271–277. https://doi.org/10.1046/j.1523-1755.1999.00252.x
Huang L-T, Tiao M-M, Tain Y-L, Chen C-C, Hsieh C-S (2009) Melatonin ameliorates bile duct ligation-induced systemic oxidative stress and spatial memory deficits in developing rats. Pediatr Res 65:176–180. https://doi.org/10.1203/PDR.0b013e31818d5bc7
Jamshidzadeh A, Heidari R, Abasvali M, Zarei M, Ommati MM, Abdoli N, Khodaei F, Yeganeh Y, Jafari F, Zarei A, Latifpour Z, Mardani E, Azarpira N, Asadi B, Najibi A (2017a) Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia. Biomed Pharmacother 86:514–520. https://doi.org/10.1016/j.biopha.2016.11.095
Jamshidzadeh A, Heidari R, Latifpour Z, Ommati MM, Abdoli N, Mousavi S, Azarpira N, Zarei A, Zarei M, Asadi B, Abasvali M, Yeganeh Y, Jafari F, Saeedi A, Najibi A, Mardani E (2017b) Carnosine ameliorates liver fibrosis and hyperammonemia in cirrhotic rats. Clin Res Hepatol Gastroenterol 41:424–434. https://doi.org/10.1016/j.clinre.2016.12.010
Kalinina TS, Bannova AV, Dygalo NN (2002) Quantitative evaluation of DNA fragmentation. Bull Exp Biol Med 134:554–556. https://doi.org/10.1023/A:1022957011153
Krones E, Pollheimer MJ, Rosenkranz AR, Fickert P (2018) Cholemic nephropathy – historical notes and novel perspectives. Biochim Biophys Acta Mol basis Dis 1864:1356–1366. https://doi.org/10.1016/j.bbadis.2017.08.028
Krones E, Wagner M, Eller K, Rosenkranz AR, Trauner M, Fickert P (2015) Bile acid-induced cholemic nephropathy. Dig Dis 33:367–375. https://doi.org/10.1159/000371689
Kurien BT, Everds NE, Scofield RH (2004) Experimental animal urine collection: a review. Lab Anim 38:333–361. https://doi.org/10.1258/0023677041958945
Lino M, Binaut R, Noël L-H, Patey N, Rustin P, Daniel L, Serpaggi J, Varaut A, Vanhille P, Knebelmann B, Grünfeld J-P, Fakhouri F (2005) Tubulointerstitial nephritis and Fanconi syndrome in primary biliary cirrhosis. Am J Kidney Dis 46:e41–e46. https://doi.org/10.1053/j.ajkd.2005.05.021
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Malik SG, Irwanto KA, Ostrow JD, Tiribelli C (2010) Effect of bilirubin on cytochrome C oxidase activity of mitochondria from mouse brain and liver. BMC Res Notes 3:162. https://doi.org/10.1186/1756-0500-3-162
Mandorfer M, Hecking M (2019) The renaissance of cholemic nephropathy: a likely underestimated cause of renal dysfunction in liver disease. Hepatology 69:1858–1860. https://doi.org/10.1002/hep.30558
Manucha W (2014) HSP70 family in the renal inflammatory response. Inflamm Allergy Drug Targets 13:235–240. https://doi.org/10.2174/1871528113666140805125632
Meyer K, Buettner S, Ghezzi D, Zeviani M, Bano D, Nicotera P (2015) Loss of apoptosis-inducing factor critically affects MIA40 function. Cell Death Dis 6:e1814–e1814. https://doi.org/10.1038/cddis.2015.170
Millan A, Huerta S (2009) Apoptosis-inducing factor and colon cancer. J Surg Res 151:163–170. https://doi.org/10.1016/j.jss.2007.05.020
Mitchell C, Mahrouf-Yorgov M, Mayeuf A, Robin M-A, Mansouri A, Fromenty B, Gilgenkrantz H (2011) Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease. Lab Investig 91:273–282. https://doi.org/10.1038/labinvest.2010.163
Modjtahedi N, Giordanetto F, Madeo F, Kroemer G (2006) Apoptosis-inducing factor: vital and lethal. Trends Cell Biol 16:264–272. https://doi.org/10.1016/j.tcb.2006.03.008
Mormone E, George J, Nieto N (2011) Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem Biol Interact 193:225–231. https://doi.org/10.1016/j.cbi.2011.07.001
Morton SU, Prabhu SP, Lidov HGW, Shi J, Anselm I, Brownstein CA, Bainbridge MN, Beggs AH, Vargas SO, Agrawal PB (2017) AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant. Cold Spring Harbor Molecular Case Studies 3:a001560. https://doi.org/10.1101/mcs.a001560
Mustafa MG, Cowger ML, King TE (1969) Effects of bilirubin on mitochondrial reactions. J Biol Chem 244:6403–6414
Norberg E, Orrenius S, Zhivotovsky B (2010) Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). Biochem Biophys Res Commun 396:95–100. https://doi.org/10.1016/j.bbrc.2010.02.163
O'Brien A, China L, Massey KA, Nicolaou A, Winstanley A, Newson J, Hobbs A, Audzevich T, Gilroy DW (2016) Bile duct-ligated mice exhibit multiple phenotypic similarities to acute decompensation patients despite histological differences. Liver Int 36:837–846. https://doi.org/10.1111/liv.12876
Ommati MM, Amjadinia A, Mousavi K, Azarpira N, Jamshidzadeh A, Heidari R (2020a) N-Acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats. Stress: 1-16. https://doi.org/10.1080/10253890.2020.1777970
Ommati MM, Farshad O, Azarpira N, Shafaghat M, Niknahad H, Heidari R (2020b) Betaine alleviates cholestasis-associated renal injury by mitigating oxidative stress and enhancing mitochondrial function. Biologia: In-Press. https://doi.org/10.2478/s11756-020-00576-x
Ommati MM, Farshad O, Mousavi K, Taghavi R, Farajvajari S, Azarpira N, Moezi L, Heidari R (2020c) Agmatine alleviates hepatic and renal injury in a rat model of obstructive jaundice. PharmaNutrition 13:100212. https://doi.org/10.1016/j.phanu.2020.100212
Ommati MM, Heidari R, Ghanbarinejad V, Aminian A, Abdoli N, Niknahad H (2019) The neuroprotective properties of carnosine in a mouse model of manganism is mediated via mitochondria regulating and antioxidative mechanisms. Nutr Neurosci 23:731–743. https://doi.org/10.1080/1028415X.2018.1552399
Orellana M, Rodrigo R, Thielemann L, Guajardo V (2000) Bile duct ligation and oxidative stress in the rat: effects in liver and kidney. Comp Biochem Physiol Pharmacol Toxicol Endocrinol 126:105–111. https://doi.org/10.1016/S0742-8413(00)00102-X
Otera H, Ohsakaya S, Nagaura Z-I, Ishihara N, Mihara K (2005) Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. EMBO J 24:1375–1386. https://doi.org/10.1038/sj.emboj.7600614
Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922. https://doi.org/10.1007/s10495-007-0756-2
Palmeira CM, Rolo AP (2004) Mitochondrially-mediated toxicity of bile acids. Toxicology 203:1–15. https://doi.org/10.1016/j.tox.2004.06.001
Patil A, Mayo MJ (2008) Complications of cholestasis. In: Md JAT (ed) Md KDL. Humana Press, Cholestatic liver disease, pp 155–169
Perez MJ, Briz O (2009) Bile-acid-induced cell injury and protection. W J Gastroenterol 15:1677–1689. https://doi.org/10.3748/wjg.15.1677
Poli G (2000) Pathogenesis of liver fibrosis: role of oxidative stress. Mol Asp Med 21:49–98. https://doi.org/10.1016/s0098-2997(00)00004-2
Portincasa P, Grattagliano I, Testini M, Caruso ML, Wang DQH, Moschetta A, Calamita G, Vacca M, Valentini AM, Renna G, Lissidini G, Palasciano G (2007) Parallel intestinal and liver injury during early cholestasis in the rat: modulation by bile salts and antioxidants. Free Radic Biol Med 42:1381–1391. https://doi.org/10.1016/j.freeradbiomed.2007.01.039
Qu B-G, Wang H, Jia Y-G, Su J-L, Wang Z-D, Wang Y-F, Han X-H, Liu Y-X, Pan J-D, Ren G-Y (2015) Changes in tumor necrosis factor-α, heat shock protein 70, malondialdehyde, and superoxide dismutase in patients with different severities of alcoholic fatty liver disease. Medicine 94:e643. https://doi.org/10.1097/MD.0000000000000643
Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jäättelä M, Penninger JM, Garrido C, Kroemer G (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843. https://doi.org/10.1038/ncb0901-839
Ravindran S, Jahir Hussain S, Boovarahan SR, Kurian GA (2017) Sodium thiosulfate post-conditioning protects rat hearts against ischemia reperfusion injury via reduction of apoptosis and oxidative stress. Chem Biol Interact 274:24–34. https://doi.org/10.1016/j.cbi.2017.07.002
Rodríguez-Garay EA (2003) Cholestasis: human disease and experimental animal models. Ann Hepatol 2:150–158. https://doi.org/10.1016/S1665-2681(19)32126-X
Rolo AP, Palmeira CM, Wallace KB (2003) Mitochondrially mediated synergistic cell killing by bile acids. Biochim Biophys Acta 1637:127–132. https://doi.org/10.1016/S0925-4439(02)00224-7
Schulz S, Schmitt S, Wimmer R, Aichler M, Eisenhofer S, Lichtmannegger J, Eberhagen C, Artmann R, Tookos F, Walch A, Krappmann D, Brenner C, Rust C, Zischka H (2013) Progressive stages of mitochondrial destruction caused by cell toxic bile salts. Biochim Biophys Acta 1828:2121–2133. https://doi.org/10.1016/j.bbamem.2013.05.007
Sevrioukova IF (2011) Apoptosis-inducing factor: structure, function, and redox regulation. Antioxid Redox Signal 14:2545–2579. https://doi.org/10.1089/ars.2010.3445
Sheen J-M, Chen Y-C, Hsu M-H, Tain Y-L, Huang Y-H, Tiao M-M, Li S-W, Huang L-T (2016) Melatonin alleviates liver apoptosis in bile duct ligation young rats. Int J Mol Sci 17:1365. https://doi.org/10.3390/ijms17081365
Sheen J-M, Huang L-T, Hsieh C-S, Chen C-C, Wang J-Y, Tain Y-L (2010) Bile duct ligation in developing rats: temporal progression of liver, kidney, and brain damage. J Pediatr Surg 45:1650–1658. https://doi.org/10.1016/j.jpedsurg.2009.12.019
Shelar SB, Kaminska KK, Reddy SA, Kumar D, Tan C-T, Yu VC, Lu J, Holmgren A, Hagen T, Chew E-H (2015) Thioredoxin-dependent regulation of AIF-mediated DNA damage. Free Radic Biol Med 87:125–136. https://doi.org/10.1016/j.freeradbiomed.2015.06.029
Silver JT, Noble EG (2012) Regulation of survival gene HSP70. Cell Stress Chaperones 17:1–9. https://doi.org/10.1007/s12192-011-0290-6
Sokol RJ, Devereaux M, Khandwala RA (1991) Effect of dietary lipid and vitamin E on mitochondrial lipid peroxidation and hepatic injury in the bile duct-ligated rat. J Lipid Res 32:1349–1357
Vaz AR, Delgado-Esteban M, Brito MA, Bolaños JP, Brites D, Almeida A (2010) Bilirubin selectively inhibits cytochrome c oxidase activity and induces apoptosis in immature cortical neurons: assessment of the protective effects of glycoursodeoxycholic acid. J Neurochem 112:56–65. https://doi.org/10.1111/j.1471-4159.2009.06429.x
Wang Y, Kim NS, Haince J-F, Kang HC, David KK, Andrabi SA, Poirier GG, Dawson VL, Dawson TM (2011) Poly (ADP-ribose)(PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1–dependent cell death (parthanatos). Sci Signal 4:ra20–ra20. https://doi.org/10.1126/scisignal.2000902
Yeh C-H, Hsu S-P, Yang C-C, Chien C-T, Wang N-P (2010) Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci 86:115–123. https://doi.org/10.1016/j.lfs.2009.11.022
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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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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 394, 1191–1203 (2021). https://doi.org/10.1007/s00210-020-02041-7
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DOI: https://doi.org/10.1007/s00210-020-02041-7