Protective role of alpha-lipoic acid against rhabdomyolysis-induced acute kidney injury in rats

Document Type : Original Article


1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Pathology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran



Objective(s): Rhabdomyolysis, a potentially life-threatening condition, occurs when myoglobin is released from damaged muscle cells, leading to acute kidney injury (AKI). Alpha lipoic acid (ALA), an organosulfur compound known for its anti-oxidant and anti-inflammatory properties, was examined in this study for its potential impact on rhabdomyolysis-induced AKI in rats. 
Materials and Methods: Six groups of rats were included in the study, with each group consisting of six rats (n=6): Control, rhabdomyolysis, rhabdomyolysis treated with different doses of ALA (5, 10, and 20 mg/kg), and ALA alone (20 mg/kg) groups. Rhabdomyolysis was induced by intramuscular injection of glycerol on the first day of the experiment, while ALA was administered intraperitoneally for four consecutive days. Renal function parameters, oxidative stress markers, and histological changes in the kidneys were evaluated. Western blot analysis was performed to measure the levels of neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-alpha (TNF-α) proteins.
Results: A significant increase in serum urea, creatinine, renal malondialdehyde, NGAl, and TNF-α protein levels was observed in glycerol-injected rats. In addition, a significant decrease in glutathione was recorded. Compared to the rhabdomyolysis group, treatment with ALA recovered kidney histological and biochemical abnormalities. 
Conclusion: Results suggest that rhabdomyolysis-induced AKI is associated with increased oxidative stress and inflammation. Treatment with ALA improved kidney histological abnormalities and reduced oxidative stress markers in rats. Therefore, ALA may have a potential protective effect against rhabdomyolysis-induced AKI. 


Main Subjects

1. Daher EF, Lima RS, Silva GB Junior, Almeida JP, Siqueira FJ, Santos SQ, et al. Acute kidney injury due to rhabdomyolysis-associated gangrenous myositis. Acta Biomed 2008;79:246-250.
2. Chavez LO, Leon M, Einav S, Varon J. Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice. Criti Care 2016; 20: 1-11.
3. Panizo N, Rubio-Navarro A, Amaro-Villalobos JM, Egido J, Moreno JA. Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury. Kidney  Blood Press Res 2015; 40: 520–532. 
4. Abd-Ellatif RN, Hegab II, Atef MM, Sadek MT, Hafez YM. Diacerein protects against glycerol induced acute kidney injury: Modulating oxidative stress, inflammation, apoptosis and necroptosis. Chem Biol Interact 2019; 306:47–53. 
5. De Jesus Soares T, Volpini RA, Francescato HD, Costa RS, da Silva CG, Coimbra TM. Effects of resveratrol on glycerol-induced renal injury. Life Sci 2007; 81:647–656. 
6. Wei Q, Hill WD, Su Y, Huang S, Dong Z. Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury. Am J Physiol Renal Physiol 2011; 301: 162–170. 
7. Kim JH, Lee SS, Jung MH, Yeo HD, Kim HJ, Yang JI, et al. N-acetylcysteine attenuates glycerol-induced acute kidney injury by regulating MAPKs and Bcl-2 family proteins. Nephrol Dial Transplant 2010; 25: 1435–1443. 
8. Singh AP, Junemann A, Muthuraman A, Jaggi AS, Singh N, Grover K, et al. Animal models of acute renal failure. Pharmacol Repo 2012; 64:31–44. 
9. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med 2009; 361:62–72. 
10. Homsi E, Janino P, de Faria JB. Role of caspases on cell death, inflammation, and cell cycle in glycerol-induced acute renal failure. Kidney Int 2006; 69: 1385–1392. 
11. Homsi E, Mota da Silva S Jr., Machado de Brito S, Boucada Inacio Peixoto E, Butori Lopes de Faria J, Janino P. p53-Mediated oxidative stress and tubular injury in rats with glycerol-induced acute kidney injury. Am J Nephrol 2011; 33:49–59. 
12. Yin M, Jiang N, Guo L, Ni Z, Al-Brakati AY, Othman MS, et al. Oleuropein suppresses oxidative, inflammatory, and apoptotic responses following glycerol-induced acute kidney injury in rats. Life Sci 2019; 232:116634.
13. Boozari M, Hosseinzadeh H. Natural medicines for acute renal failure: A review. Phytother Res. 2017; 31:1824-1835.
14. Zhang J, McCullough PA. Lipoic acid in the prevention of acute kidney injury. Nephron 2016; 134:133–140. 
15. Cronan JE. Progress in the enzymology of the mitochondrial diseases of lipoic acid requiring enzymes. Front Genet 2020; 11: 1-6. 
16. Seifar F, Khalili M, Khaledyan H, Amiri Moghadam Sh, Izadi A, Azimi, A.  α-Lipoic acid, functional fatty acid, as a novel therapeutic alternative for central nervous system diseases: A review. Nutr Neurosci 2019; 22:306–316.
17. Theodosis-Nobelos P, Papagiouvannis G, Tziona P, Rekka EA.  Lipoic acid: Kinetics and pluripotent biological properties and derivatives. Mol Biol Rep 2021; 48:6539–6550.
18. Petronilho F, Florentino D, Danielski LG, Vieira LC, Martins MM, Vieira A, et al. Alpha- Lipoic acid attenuates oxidative damage in organs after sepsis. Inflammation 2016; 39:357–365. 
19. AlBasher G, Alfarraj S, Alarifi S, Alkhtani S, Almeer R, Alsultan N, et al. Nephroprotective role of selenium nanoparticles against glycerol-induced acute kidney injury in rats. Biol Trace Elem Res 2020; 194:444–454.
20. Al Abdan M. Alfa-lipoic acid controls tumor growth and modulates hepatic redox state in Ehrlich-ascites-carcinoma-bearing mice. SciWorld J 2012; 2012:1-6. 
21. Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr 2014; 6:1-8.
22. Calderone L, Grimes P, Shalev M. Acute reversible cataract induced by xylazine and by ketamine-xylazine anesthesia in rats and mice. Exp Eye Res 1986; 42:331-337.
23. Liano F, Pascual J; Group MARFS. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Kidney Int 1996; 50:811-818.
24. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86:271-278.
25. Ghasemzadeh Rahbardar M, Cheraghi Farmad H, Hosseinzadeh H, Mehri S. Protective effects of selenium on acrylamide-induced neurotoxicity and hepatotoxicity in rats. Iran J Basic Med Sci 2021; 24:1041-1049 
26. Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta. 1979; 582:67-78.
27. Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Investigating the ameliorative effect of alpha-mangostin on development and existing pain in a rat model of neuropathic pain. Phytother Res 2020; 34:3211-3225.
28. Ardakanian A, Ghasemzadeh Rahbardar M, Omidkhoda F, Razavi BM, Hosseinzadeh H. Effect of alpha-mangostin on olanzapine-induced metabolic disorders in rats. Iran J Basic Med Sci 2022; 25:198-207.
29. Makris K, Spanou L. Acute kidney injury: Definition, pathophysiology and clinical phenotypes. Clin Biochem Rev 2016; 37:85-98.
30. Hareedy MS, Abdelzaher LA, Badary DM, Mohammed Alnasser S, Abd-Eldayem AM. Valproate attenuates hypertonic glycerol-induced rhabdomyolysis and acute kidney injury. Nephrol Ther 2021; 17: 160-167. 
31. Li G, Gao L, Jia J, Gong X, Zang B, Chen W. α‐Lipoic acid prolongs survival and attenuates acute kidney injury in a rat model of sepsis. Clin Exp Pharmacol Physiol 2014; 41:459-468.
32.  Asci H, Saygin M, Cankara FN, Bayram D, Yesilot S, Candan IA, et al. The impact of alpha-lipoic acid on amikacin-induced nephrotoxicity. Ren Fail 2015; 37:117-121. 
33. Reis NG, Francescato HD, de Almeida LF, Silva CG, Costa RS, Coimbra TM. Protective effect of calcitriol on rhabdomyolysis-induced acute kidney injury in rats. Sci Rep 2019; 9: 1-10.
34. Nara A, Yajima D, Nagasawa S, Abe H, Hoshioka Y, Iwase H. Evaluations of lipid peroxidation and inflammation in short‐term glycerol‐induced acute kidney injury in rats. Clin Exp Pharmacol Physiol 2016; 43:1080-1086.
35.  Suh SH, Lee KE, Kim IJ, Kim O, Kim CS, Choi JS, et al. Alpha-lipoic acid attenuates lipopolysaccharide-induced kidney injury. Clin Exp Nephrol 2015; 19:82-91. 
36. Takaoka M, Ohkita M, Kobayashi Y, Yuba M, Matsumura Y. Protective Effect Of α‐LIPOIC Acid Against Ischaemic Acute Renal Failure in Rats. Clin Exp Pharmacol Physiol 2002; 29:189-94.
37. Homsi E, Andreazzi DD, Faria JB, Janino P. TNF-α-mediated cardiorenal injury after rhabdomyolysis in rats. Am J Physiol Renal Physiol 2015; 308: 1259-1267.
38.Erdem Guzel E, Kaya Tektemur N, Tektemur A. Alpha‐lipoic acid may ameliorate testicular damage by targeting dox-induced altered anti-oxidant parameters, mitofusin-2 and apoptotic gene expression. Andrologia 2021; 53:e13990.
39. Pianta TJ, Succar L, Davidson T, Buckley NA, Endre ZH. Monitoring treatment of acute kidney injury with damage biomarkers. Toxicol Lett 2017; 268:63-70.
40. El-Sayed ES, Mansour AM, El-Sawy WS. Alpha lipoic acid prevents doxorubicin-induced nephrotoxicity by mitigation of oxidative stress, inflammation, and apoptosis in rats. J Biochem Mol Toxicol 2017 ;31:e21940.
41. Baer PC, Koch B, Geiger H. Kidney inflammation, injury and regeneration. Int J Mol Sci 2020; 21:1-4. 
42. Skibska B, Kochan E, Stanczak A, Lipert A, Skibska A. Anti-oxidant and anti-inflammatory effects of α-Lipoic Acid on lipopolysaccharide-induced oxidative stress in rat kidney. Arch Immunol Ther Exp 2023 ;71: 16.
43. Singer E, Marko L, Paragas N, Barasch J, Dragun D, Muller DN, et al. Neutrophil gelatinase-associated lipocalin: pathophysiology and clinical applications. Acta Physiol 2013; 207:663-672. 
44. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 2002; 10:1033-1043.
45. Jia J, Gong X, Zhao Y, Yang Z, Ji K, Luan T, et al. Autophagy enhancing contributes to the organ protective effect of alpha-lipoic acid in septic rats. Front Immunol 2019 2; 10:1-13.