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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Research Article

Astragaloside IV Protects Sepsis-induced Acute Kidney Injury by Attenuating Mitochondrial Dysfunction and Apoptosis in Renal Tubular Epithelial Cells

Author(s): Meixia Feng, Juan Lv, Chenxi Zhang, Dagui Chen, Huan Guo, Ye Tu*, Li Su* and Zhibin Wang*

Volume 28, Issue 34, 2022

Published on: 22 September, 2022

Page: [2825 - 2834] Pages: 10

DOI: 10.2174/1381612828666220902123755

Price: $65


Background: Acute kidney injury (AKI) is closely linked to the pathogenesis of sepsis. Oxidative stress can affect the development of AKI by increasing damage to renal tubular epithelial cells. Astragaloside IV (AS-IV) is a natural saponin widly verified beneficial for ameliorating sepsis-induced kidney injury. However, the underlying mechanisms of AS-IV on relieving oxidative stress in renal tubular epithelial cells are yet to be established.

Purpose: We aimed to investigate whether AS-IV could attenuate mitochondrialdysfunction and apoptosis in renal tubular epithelial cells and reveal its underlying mechanisms.

Methods: For the in vivo study, mice were divided into four groups (n=6): sham+saline, CLP+saline, CLP+ASIV- low dosage (5 mg/kg), CLP+AS-IV-high dosage (10 mg/kg), After 6 h or 24 h of treatment, the renal injuries were assessed based on related parameters of blood, protein and histopathological examination. Immunohistochemistry and ELISA were used to examine renal function. The molecular mechanism of AS-IV inhibited apoptosis and mitochondrial damage were monitored by flow cytometry and western blot analysis in HK-2 cells.

Results: We found that AS-IV ameliorates renal vacuolization, brush border loss, mitochondrial ultrastructure changes in sepsis-induced AKI, and the apoptosis and oxidative damage were greatly mitigated by AS-IV (10 mg/kg)-treated group. Abnormal changes in mitochondrial morphology and mitochondrial membrane potential were alleviated, and the expression of mitochondrial complex protein I (NDUFB8) and mitochondrial complex protein II (SDHB8) increased with (10 mg/kg)-treated group. Tubular epithelial cell apoptosis in AS-IV (20 μM)-treated cells was reduced by the Bax and cleaved caspase3 pathway.

Conclusion: These studies demonstrated that AS-IV protects against sepsis-induced kidney tubular injury by alleviating oxidative stress, mitochondrial dysfunction possibly associated with the restored cleaved caspase3 pathway.

Keywords: Astragaloside IV, sepsis, acute kidney injury, oxidative stress, mitochondrial dysfunction, cleaved caspase-3.

Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and assessing new clinical criteria for septic shock. JAMA 2016; 315(8): 775-87.
[] [PMID: 26903336]
Kellum JA, Prowle JR. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol 2018; 14(4): 217-30.
[] [PMID: 29355173]
Bouchard J, Acharya A, Cerda J, et al. A prospective international multicenter study of AKI in the intensive care unit. Clin J Am Soc Nephrol 2015; 10(8): 1324-31.
[] [PMID: 26195505]
Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34(2): 344-53.
[] [PMID: 16424713]
Zarbock A, Gomez H, Kellum JA. Sepsis-induced acute kidney injury revisited. Curr Opin Crit Care 2014; 20(6): 588-95.
[] [PMID: 25320909]
Takasu O, Gaut JP, Watanabe E, et al. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 2013; 187(5): 509-17.
[] [PMID: 23348975]
Gomez H, Ince C, De Backer D, et al. A unified theory of sepsis-induced acute kidney injury: Inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 2014; 41(1): 3-11.
[] [PMID: 24346647]
Mariano F, Cantaluppi V, Stella M, et al. Circulating plasma factors induce tubular and glomerular alterations in septic burns patients. Crit Care 2008; 12(2): R42.
[] [PMID: 18364044]
Su L, Zhang J, Gomez H, Kellum JA, Peng Z. Mitochondria ROS and mitophagy in acute kidney injury. Autophagy 2022; 9(4): 1-14.
Rovcanin B, Medic B, Kocic G, Cebovic T, Ristic M, Prostran M. Molecular dissection of renal ischemia-reperfusion: Oxidative stress and cellular events. Curr Med Chem 2016; 23(19): 1965-80.
[] [PMID: 26758795]
Agarwal A, Dong Z, Harris R, et al. Cellular and molecular mechanisms of AKI. J Am Soc Nephrol 2016; 27(5): 1288-99.
[] [PMID: 26860342]
Pavlakou P, Liakopoulos V, Eleftheriadis T, Mitsis M, Dounousi E. Oxidative stress and acute kidney injury in critical illness: Pathophysiologic mechanisms-biomarkers-interventions, and future perspectives. Oxid Med Cell Longev 2017; 2017: 1-11.
[] [PMID: 29104728]
Quoilin C, Mouithys-Mickalad A, Lécart S, Fontaine-Aupart MP, Hoebeke M. Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury. Biochim Biophys Acta Bioenerg 2014; 1837(10): 1790-800.
[] [PMID: 25019585]
Rimessi A, Previati M, Nigro F, Wieckowski MR, Pinton P. Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies. Int J Biochem Cell Biol 2016; 81(Pt B): 281-93.
[] [PMID: 27373679]
Nowak G, Clifton GL, Godwin ML, Bakajsova D. Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells. Am J Physiol Renal Physiol 2006; 291(4): F840-55.
[] [PMID: 16705147]
Galley HF. Bench-to-bedside review: Targeting antioxidants to mitochondria in sepsis. Crit Care 2010; 14(4): 230.
[] [PMID: 20804578]
Zhong X, He J, Zhang X, et al. UCP2 alleviates tubular epithelial cell apoptosis in lipopolysaccharide-induced acute kidney injury by decreasing ROS production. Biomed Pharmacother 2019; 115: 108914.
[] [PMID: 31071510]
Plotnikov E, Pevzner I, Zorova L, et al. Mitochondrial damage and mitochondria-targeted antioxidant protection in LPS-induced acute kidney injury. Antioxidants 2019; 8(6): 176-89.
[] [PMID: 31197113]
Yan W, Xu Y, Yuan Y, et al. Renoprotective mechanisms of Astragaloside IV in cisplatin-induced acute kidney injury. Free Radic Res 2017; 51(7-8): 669-83.
[] [PMID: 28750561]
Xu W, Shao X, Tian L, et al. Astragaloside IV ameliorates renal fibrosis via the inhibition of mitogen-activated protein kinases and antiapoptosis in vivo and in vitro. J Pharmacol Exp Ther 2014; 350(3): 552-62.
[] [PMID: 24951279]
Wang Q, Shao X, Xu W, et al. Astragalosides IV inhibits high glucose-induced cell apoptosis through HGF activation in cultured human tubular epithelial cells. Ren Fail 2014; 36(3): 400-6.
[] [PMID: 24392874]
Chen Q, Su Y, Ju Y, Ma K, Li W, Li W. Astragalosides IV protected the renal tubular epithelial cells from free fatty acids-induced injury by reducing oxidative stress and apoptosis. Biomed Pharmacother 2018; 108: 679-86.
[] [PMID: 30245468]
Ju Y, Su Y, Chen Q, et al. Protective effects of Astragaloside IV on endoplasmic reticulum stress-induced renal tubular epithelial cells apoptosis in type 2 diabetic nephropathy rats. Biomed Pharmacother 2019; 109: 84-92.
[] [PMID: 30396095]
Che X, Wang Q, Xie Y, et al. Astragaloside IV suppresses transforming growth factor-β1 induced fibrosis of cultured mouse renal fibroblasts via inhibition of the MAPK and NF-κB signaling pathways. Biochem Biophys Res Commun 2015; 464(4): 1260-6.
[] [PMID: 26220342]
Tan S, Wang G, Guo Y, Gui D, Wang N. Preventive Effects of a Natural Anti-Inflammatory Agent, Astragaloside IV, on Ischemic Acute Kidney Injury in Rats. Evid Based Complement Alternat Med 2013; 2013: 1-12.
[] [PMID: 23853656]
Zhou W, Chen Y, Zhang X, Astragaloside IV, Astragaloside IV. Alleviates lipopolysaccharide-induced acute kidney injury through down-regulating cytokines, CCR5 and p-ERK, and elevating anti-oxidative ability. Med Sci Monit 2017; 23: 1413-20.
[] [PMID: 28328867]
Luo Y, Wan Q, Xu M, et al. Nutritional preconditioning induced by astragaloside IV on isolated hearts and cardiomyocytes against myocardial ischemia injury via improving Bcl-2-mediated mitochondrial function. Chem Biol Interact 2019; 309: 108723.
[] [PMID: 31228469]
Li Y, Yang Y, Zhao Y, et al. Astragaloside IV reduces neuronal apoptosis and parthanatos in ischemic injury by preserving mitochondrial hexokinase-II. Free Radic Biol Med 2019; 131: 251-63.
[] [PMID: 30502455]
Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 2009; 4(1): 31-6.
[] [PMID: 19131954]
Sureshbabu A, Patino E, Ma KC, et al. RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction. JCI Insight 2018; 3(11): e98411.
[] [PMID: 29875323]
Hill BG, Benavides GA, Lancaster JR Jr, et al. Integration of cellular bioenergetics with mitochondrial quality control and autophagy. bchm 2012; 393(12): 1485-512.
[] [PMID: 23092819]
Hoste EAJ, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015; 41(8): 1411-23.
[] [PMID: 26162677]
Kellum JA, Chawla LS, Keener C, et al. The effects of alternative resuscitation strategies on acute kidney injury in patients with septic shock. Am J Respir Crit Care Med 2016; 193(3): 281-7.
[] [PMID: 26398704]
Castellano G, Stasi A, Intini A, et al. Endothelial dysfunction and renal fibrosis in endotoxemia-induced oliguric kidney injury: Possible role of LPS-binding protein. Crit Care 2014; 18(5): 520-38.
[] [PMID: 25261195]
Peerapornratana S, Manrique-Caballero CL, Gómez H, Kellum JA. Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int 2019; 96(5): 1083-99.
[] [PMID: 31443997]
Velez JCQ, Therapondos G, Juncos LA. Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat Rev Nephrol 2020; 16(3): 137-55.
Parikh SM. Therapeutic targeting of the mitochondrial dysfunction in septic acute kidney injury. Curr Opin Crit Care 2013; 19(6): 554-9.
[] [PMID: 24150113]
Liu J, Yang C, Zhang W, et al. Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury. Life Sci 2019; 235: 116828.
[] [PMID: 31479679]
Ren S, Zhang H, Mu Y, Sun M, Liu P. Pharmacological effects of Astragaloside IV: A literature review. J Tradit Chin Med 2013; 33(3): 413-6.
[] [PMID: 24024343]
Gui D, Huang J, Guo Y, et al. Astragaloside IV ameliorates renal injury in streptozotocin-induced diabetic rats through inhibiting NF-κB-mediated inflammatory genes expression. Cytokine 2013; 61(3): 970-7.
[] [PMID: 23434274]
Gui D, Huang J, Liu W, Guo Y, Xiao W, Wang N. Astragaloside IV prevents acute kidney injury in two rodent models by inhibiting oxidative stress and apoptosis pathways. Apoptosis 2013; 18(4): 409-22.
[] [PMID: 23325448]
Buelli S, Locatelli M, Carminati CE, et al. Shiga Toxin 2 triggers C3a-dependent glomerular and tubular injury through mitochondrial dysfunction in hemolytic uremic syndrome. Cells 2022; 11(11): 1755.
[] [PMID: 35681450]
Hu Y, Tang W, Liu W, et al. Alleviates renal tubular epithelial-mesenchymal transition via CX3CL1-RAF/MEK/ERK signaling pathway in diabetic kidney disease. Drug Des Devel Ther 2022; 16: 1605-20.
[] [PMID: 35669284]
Wang YN, Zhao SL, Su YY, et al. Astragaloside IV attenuates high glucose-induced EMT by inhibiting the TGF-β/Smad pathway in renal proximal tubular epithelial cells. Biosci Rep 2020; 40(6): BSR20190987.
[] [PMID: 32515466]
Mapuskar KA, Wen H, Holanda DG, et al. Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease. Redox Biol 2019; 20: 98-106.
[] [PMID: 30296702]
Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 2002; 30(2): 276-84.
[] [PMID: 11889292]
Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ, De Wolf-Peeters C, Van den Berghe G. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005; 365(9453): 53-9.
[] [PMID: 15639679]
Fani F, Regolisti G, Delsante M, et al. Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. J Nephrol 2018; 31(3): 351-9.
[] [PMID: 29273917]
Nakahira K, Kyung SY, Rogers AJ, et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: Derivation and validation. PLoS Med 2013; 10(12): e1001577.
[] [PMID: 24391478]
Lerolle N, Nochy D, Guérot E, et al. Histopathology of septic shock induced acute kidney injury: Apoptosis and leukocytic infiltration. Intensive Care Med 2010; 36(3): 471-8.
[] [PMID: 19924395]
Jo SK, Cha DR, Cho WY, et al. Inflammatory cytokines and lipopolysaccharide induce Fas-mediated apoptosis in renal tubular cells. Nephron J 2002; 91(3): 406-15.
[] [PMID: 12119470]
Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15(22): 2922-33.
[PMID: 11711427]
Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ 2000; 7(12): 1182-91.
[] [PMID: 11175255]
Li Q, Li J, Shao H, Li XX, Yu F, Xu M. Inhibition of CPU0213, a dual endothelin receptor antagonist, on apoptosis via Nox4-dependent ROS in HK-2 cells. Cell Physiol Biochem 2016; 39(1): 183-92.
[] [PMID: 27336467]

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