Preconditioning by Moderate-Intensity Exercise Prevents Gentamicin-Induced Acute Kidney Injury

Abstract

A strict correlation among proximal tubule epithelial cell dysfunction, proteinuria, and modulation of the Renin-Angiotensin System and Kalikrein-Kinin System are crucial factors in the pathogenesis of Acute Kidney Injury (AKI). In this study, we investigated the potential protective effect of preconditioning by moderate-intensity aerobic exercise on gentamicin-induced AKI. Male Wistar rats were submitted to a moderate-intensity treadmill exercise protocol for 8 weeks, and then injected with 80 mg/kg/day s.c. gentamicin for 5 consecutive days. Four groups were generated: 1) NT+SAL (control); 2) NT+AKI (non-trained with AKI); 3) T+SAL (trained); and 4) T+AKI (trained with AKI). The NT+AKI group presented: 1) impairment in glomerular function parameters; 2) increased fractional excretion of Na ⁺ , K ⁺ , and water; 4) proteinuria and increased urinary γ-glutamyl transferase activity (a marker of tubular injury) accompanied by acute tubular necrosis; 5) an increased renal angiotensin-converting enzyme and bradykinin B1 receptor mRNA expression. Interestingly, the preconditioning by moderate-intensity aerobic exercise attenuated all alterations observed in gentamicin-induced AKI (T+AKI group). Taken together, our results show that the preconditioning by moderate-intensity aerobic exercise ameliorates the development of gentamicin-induced AKI. Our findings help to expand the current knowledge regarding the effect of physical exercise on kidneys during physiological and pathological conditions.

Keywords

acute kidney injury - gentamicin - moderate-intensity aerobic exercise - proteinuria - Renin-Angiotensin System - Kallikrein-Kinin System

Publication History

Received: 05 February 2024

Accepted: 03 June 2024

Article published online:
19 July 2024

• References

• 1 Kellum JA, Romagnani P, Ashuntantang G. et al. Acute kidney injury. Nat Rev Dis Primers 2021; 7: 52
• 2 Kellum JA, Ronco C, Bellomo R. Conceptual advances and evolving terminology in acute kidney disease. Nat Rev Nephrol 2021; 17: 493-502
• 3 McWilliam SJ, Antoine DJ, Smyth RL. et al. Aminoglycoside-induced nephrotoxicity in children. Pediatr Nephrol 2017; 32: 2015-2025
• 4 Pacheco LF, de Castro CH, Dutra JBR. et al. Oral Treatment with Angiotensin-(1-7) Attenuates the Kidney Injury Induced by Gentamicin in Wistar Rats. Protein Pept Lett 2021; 28: 1425-1433
• 5 Tomşa AM, Răchişan AL, Pandrea SL. et al. Accelerated lipid peroxidation in a rat model of gentamicin nephrotoxicity. Exp Ther Med 2021; 22: 1218
• 6 Perazella MA. Drug-induced acute kidney injury: Diverse mechanisms of tubular injury. Curr Opin Crit Care 2019; 25: 550-557
• 7 Jospe-Kaufman M, Siomin L, Fridman M. The relationship between the structure and toxicity of aminoglycoside antibiotics. Bioorg Med Chem Lett 2020; 30: 127218
• 8 Huang X, Liu Y-X, Lao J-H. et al. The incidence of acute kidney injury in hospitalized patients receiving aminoglycoside antibiotics: A retrospective study. Eur Rev Med Pharmacol Sci 2022; 26: 3718-3725
• 9 Zappitelli M, Moffett BS, Hyder A. et al. Acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: A retrospective cohort study. Nephrol Dial Transplant 2011; 26: 144-150
• 10 Zorov DB. Amelioration of aminoglycoside nephrotoxicity requires protection of renal mitochondria. Kidney International 2010; 77: 841-843
• 11 Balakumar P, Rohilla A, Thangathirupathi A. Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it?. Pharmacological Research 2010; 62: 179-186
• 12 Venkatachalam MA, Weinberg JM, Kriz W. et al. Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression. J Am Soc Nephrol 2015; 26: 1765-1776
• 13 Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol 2015; 11: 264-276
• 14 Sharma N, Anders H-J, Gaikwad AB. Fiend and friend in the renin angiotensin system: An insight on acute kidney injury. Biomed Pharmacother 2019; 110: 764-774
• 15 Estrela GR, Wasinski F, Almeida DC. et al. Kinin B1 receptor deficiency attenuates cisplatin-induced acute kidney injury by modulating immune cell migration. J Mol Med (Berl) 2014; 92: 399-409
• 16 Estrela GR, Wasinski F, Bacurau RF. et al. Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Int Immunopharmacol 2014; 22: 115-119
• 17 Silva LS, Peruchetti DB, Silva-Aguiar RP. et al. The angiotensin II/AT1 receptor pathway mediates malaria-induced acute kidney injury. PLoS One 2018; 13: e0203836
• 18 Ali BH, Bashir AA. Serum angiotensin-converting enzyme activity in rats with gentamicin-induced nephrotoxicity. Nephron 1993; 64: 477-478
• 19 Heeba GH. Angiotensin II receptor blocker, losartan, ameliorates gentamicin-induced oxidative stress and nephrotoxicity in rats. Pharmacology 2011; 87: 232-240
• 20 Bledsoe G, Shen B, Yao Y-Y. et al. Role of tissue kallikrein in prevention and recovery of gentamicin-induced renal injury. Toxicol Sci 2008; 102: 433-443
• 21 Qiu Y, Fernández-García B, Lehmann HI. et al. Exercise sustains the hallmarks of health. J Sport Health Sci 2023; 12: 8-35
• 22 Rahman MM, Kwon H-S, Kim M-J. et al. Melatonin supplementation plus exercise behavior ameliorate insulin resistance, hypertension and fatigue in a rat model of type 2 diabetes mellitus. Biomed Pharmacother 2017; 92: 606-614
• 23 Menezes KK, Nascimento LR, Ada L. et al. Respiratory muscle training increases respiratory muscle strength and reduces respiratory complications after stroke: A systematic review. J Physiother 2016; 62: 138-144
• 24 Goessler KF, Martins-Pinge MC, da Cunha NV. et al. Direct renin inhibitor therapy and swimming training: Hemodynamic and cardiac effects in hypertensive and normotensive rats. Clin Exp Hypertens 2015; 37: 345-352
• 25 Goessler KF, Martins-Pinge M, Veronez da Cunha N. et al. Treatment with nebivolol combined with physical training promotes improvements in the cardiovascular responses of hypertensive rats. Can J Physiol Pharmacol 2014; 92: 234-242
• 26 Agarwal D, Elks CM, Reed SD. et al. Chronic exercise preserves renal structure and hemodynamics in spontaneously hypertensive rats. Antioxid Redox Signal 2012; 16: 139-152
• 27 de Lima WV, Visona I, Schor N. et al. Preconditioning by aerobic exercise reduces acute ischemic renal injury in rats. Physiol Rep 2019; 7: e14176
• 28 Francescato HDC, Almeida LF, Reis NG. et al. Previous Exercise Effects in Cisplatin-Induced Renal Lesions in Rats. Kidney Blood Press Res 2018; 43: 582-593
• 29 Oliveira CS, Rodrigues AM, Nogueira GB. et al. Moderate aerobic exercise on the recovery phase of gentamicin-induced acute kidney injury in rats. Life Sci 2017; 169: 37-42
• 30 Arazi H, Falahati A, Suzuki K. Moderate Intensity Aerobic Exercise Potential Favorable Effect Against COVID-19: The Role of Renin-Angiotensin System and Immunomodulatory Effects. Front Physiol 2021; 12: 747200
• 31 Frantz EDC, Medeiros RF, Giori IG. et al. Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats. Exp Physiol 2017; 102: 1208-1220
• 32 Lestari YM, Tarawan VM, Achadiyani A. et al. Exercise intensities modulate ACE2/MasR/eNOS pathway in male Wistar rat’s lung. Physiol Rep 2023; 11: e15803
• 33 Echeverría-Rodríguez O, Gallardo-Ortíz IA, Del Valle-Mondragón L. et al. Angiotensin-(1-7) Participates in Enhanced Skeletal Muscle Insulin Sensitivity After a Bout of Exercise. J Endocr Soc 2020; 4: bvaa007
• 34 Priviero F, De Nucci G, Antunes E. et al. Negative chronotropic response to adenosine receptor stimulation in rat right atria after run training. Clin Exp Pharmacol Physiol 2004; 31: 741-743
• 35 Carvalho JF, Masuda MO, Pompeu FAMS. Method for diagnosis and control of aerobic training in rats based on lactate threshold. Comp Biochem Physiol A Mol Integr Physiol 2005; 140: 409-413
• 36 Brooks GA, White TP. Determination of metabolic and heart rate responses of rats to treadmill exercise. J Appl Physiol Respir Environ Exerc Physiol 1978; 45: 1009-1015
• 37 Haugen HN. The determination of endogenous creatinine in plasma and urine. Scand J Clin Lab Invest 1953; 5: 48-57
• 38 Alp PR, Newsholme EA, Zammit VA. Activities of citrate synthase and NAD+-linked and NADP+-linked isocitrate dehydrogenase in muscle from vertebrates and invertebrates. Biochem J 1976; 154: 689-700
• 39 Vigelsø A, Andersen NB, Dela F. The relationship between skeletal muscle mitochondrial citrate synthase activity and whole body oxygen uptake adaptations in response to exercise training. Int J Physiol Pathophysiol Pharmacol 2014; 6: 84-101
• 40 Barcelos RP, Souza MA, Amaral GP. et al. Caffeine supplementation modulates oxidative stress markers in the liver of trained rats. Life Sci 2014; 96: 40-45
• 41 Cornelissen VA, Buys R, Smart NA. Endurance exercise beneficially affects ambulatory blood pressure: A systematic review and meta-analysis. J Hypertens 2013; 31: 639-648
• 42 Maron BJ, Pelliccia A. The heart of trained athletes: Cardiac remodeling and the risks of sports, including sudden death. Circulation 2006; 114: 1633-1644
• 43 D’Souza A, Bucchi A, Johnsen AB. et al. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nat Commun 2014; 5: 3775
• 44 Wichi RB, De Angelis K, Jones L. et al. A brief review of chronic exercise intervention to prevent autonomic nervous system changes during the aging process. Clinics (Sao Paulo) 2009; 64: 253-258
• 45 Boveris A, Navarro A. Systemic and mitochondrial adaptive responses to moderate exercise in rodents. Free Radic Biol Med 2008; 44: 224-229
• 46 Kawakami S, Yasuno T, Kotoku K. et al. The differences in renal hemodynamic response following high-intensity exercise between younger and older males. Clin Exp Nephrol 2023; 27: 972-980
• 47 Belli T, Macedo DV, de Araújo GG. et al. Mountain Ultramarathon Induces Early Increases of Muscle Damage, Inflammation, and Risk for Acute Renal Injury. Front Physiol 2018; 9: 1368
• 48 Lipman GS, Shea K, Christensen M. et al. Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: A randomised controlled trial. Emerg Med J 2017; 34: 637-642
• 49 Shen H, Feng C, Jin X. et al. Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review. BMC Pediatr 2014; 14: 73
• 50 Shimizu Y, Wakabayashi K, Totsuka A. et al. Exercise-Induced Acute Kidney Injury in a Police Officer with Hereditary Renal Hypouricemia. Case Rep Nephrol Dial 2019; 9: 92-101
• 51 Al Badi A, Al Rasbi S, Alalawi AM. Exercise-Induced Rhabdomyolysis: A Case Report and Literature Review. Cureus 2020; 12: e10037
• 52 Schlader ZJ, Hostler D, Parker MD. et al. The Potential for Renal Injury Elicited by Physical Work in the Heat. Nutrients 2019; 11: 2087
• 53 Húngaro TGR, Freitas-Lima LC, Gregnani MF. et al. Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4. Front Physiol 2020; 11: 768
• 54 Vallon V. Tubular Transport in Acute Kidney Injury: Relevance for Diagnosis, Prognosis and Intervention. Nephron 2016; 134: 160-166
• 55 George B, Joy MS, Aleksunes LM. Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy. Exp Biol Med (Maywood) 2018; 243: 272-282
• 56 Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage?. J Am Soc Nephrol 2006; 17: 2974-2984
• 57 Risso MA, Sallustio S, Sueiro V. et al. The Importance of Tubular Function in Chronic Kidney Disease. Int J Nephrol Renovasc Dis 2019; 12: 257-262
• 58 Peruchetti DB, Silva-Filho JL, Silva-Aguiar RP. et al. IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload. Front Physiol 2020; 11: 172
• 59 Peruchetti DB, Freitas AC, Pereira VC. et al. PKB is a central molecule in the modulation of Na+-ATPase activity by albumin in renal proximal tubule cells. Arch Biochem Biophys 2019; 674: 108115
• 60 Peruchetti DB, Barahuna-Filho PFR, Silva-Aguiar RP. et al. Megalin-mediated albumin endocytosis in renal proximal tubules is involved in the antiproteinuric effect of angiotensin II type 1 receptor blocker in a subclinical acute kidney injury animal model. Biochim Biophys Acta Gen Subj 2021; 1865: 129950
• 61 Farias RS, Silva-Aguiar RP, Teixeira DE. et al. Inhibition of SGLT2 co-transporter by dapagliflozin ameliorates tubular proteinuria and tubule-interstitial injury at the early stage of diabetic kidney disease. Eur J Pharmacol 2023; 942: 175521
• 62 Nagai J, Sato K, Yumoto R. et al. Megalin/cubilin-mediated uptake of FITC-labeled IgG by OK kidney epithelial cells. Drug Metab Pharmacokinet 2011; 26: 474-485
• 63 Dagil R, O’Shea C, Nykjær A. et al. Gentamicin binds to the megalin receptor as a competitive inhibitor using the common ligand binding motif of complement type repeats: Insight from the nmr structure of the 10th complement type repeat domain alone and in complex with gentamicin. J Biol Chem 2013; 288: 4424-4435
• 64 Balaha MF, Alamer AA, Eisa AA. et al. Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades. Antibiotics (Basel) 2023; 12: 826
• 65 Akour AA, Kennedy MJ, Gerk PM. The Role of Megalin in the Transport of Gentamicin Across BeWo Cells, an In Vitro Model of the Human Placenta. AAPS J 2015; 17: 1193-1199
• 66 Cui S, Verroust PJ, Moestrup SK. et al. Megalin/gp330 mediates uptake of albumin in renal proximal tubule. Am J Physiol 1996; 271: F900-F907
• 67 Hori Y, Aoki N, Kuwahara S. et al. Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity. J Am Soc Nephrol 2017; 28: 1783-1791
• 68 Khalifa O, Al-Sahlawi Z, Imtiaz F. et al. Variable expression pattern in Donnai-Barrow syndrome: Report of two novel LRP2 mutations and review of the literature. Eur J Med Genet 2015; 58: 293-299
• 69 Larsen CP, Trivin-Avillach C, Coles P. et al. LDL Receptor-Related Protein 2 (Megalin) as a Target Antigen in Human Kidney Anti-Brush Border Antibody Disease. J Am Soc Nephrol 2018; 29: 644-653
• 70 Al-Kuraishy HM, Al-Gareeb AI, Al-Naimi MS. Renoprotective effect of irbesartan in a rat model of gentamicin-induced nephrotoxicity: Role of oxidative stress. J Lab Physicians 2019; 11: 200-205
• 71 Bae EH, Kim IJ, Joo SY. et al. Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats. J Renin Angiotensin Aldosterone Syst 2014; 15: 348-361
• 72 Abdel-Fattah MM, Elgendy ANAM, Mohamed WR. Xanthenone, ACE2 activator, counteracted gentamicin-induced nephrotoxicity in rats: Impact on oxidative stress and ACE2/Ang-(1-7) signaling. Life Sci 2021; 275: 119387
• 73 Alves SAS, Florentino LS, Teixeira DE. et al. Surface megalin expression is a target to the inhibitory effect of bradykinin on the renal albumin endocytosis. Peptides 2021; 146: 170646
• 74 Arazi H, Mohabbat M, Saidie P. et al. Effects of Different Types of Exercise on Kidney Diseases. Sports (Basel) 2022; 10: 42
• 75 Costanti-Nascimento AC, Brelaz-Abreu L, Bragança-Jardim E. et al. Physical exercise as a friend not a foe in acute kidney diseases through immune system modulation. Front Immunol 2023; 14: 1212163