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Drug Res (Stuttg) 2021; 71(05): 243-249
DOI: 10.1055/a-1369-8651
Original Article

Evaluation of the Effect of Captopril and Losartan on Tacrolimus-induced Nephrotoxicity in Rats

Seyedeh Mahsa Poormoosavi
1   Department of Histology, School of Medicine, Research and Clinical Center for Infertility, Dezful University of Medical Sciences, Dezful, Iran
,
Mohammad Amin Behmanesh
2   Department of Histology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
,
Hamed Abeyat
3   School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
,
Ehsan Sangtarash
3   School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
› Institutsangaben Funding: The authors would like to acknowledge Dezful University for financially supported.
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Abstract

Background Tacrolimus is an immunosuppressive drug. Activation of the renin-angiotensin system (RAS) and associated inflammations may exacerbate the toxic effects of tacrolimus. Given the significant role of the kidney in RAS this study aimed to evaluate the effect of captopril as an angiotensin-converting enzyme (ACE) blocker and losartan as an angiotensin II receptor blocker on tacrolimus-induced nephrotoxicity.

Materials and Methods In total, 36 adult male rats weighing 200–250 gr were completely randomized and divided into six groups (control, tacrolimus, tacrolimus and losartan, tacrolimus and captopril, losartan, and captopril) for 30 days. Afterwards, blood urea nitrogen (BUN), creatinine (Cr) and ACE2 enzyme were measured. Also, both kidneys were collected for histological examinations.

Results The level of BUN and Cr significantly increased in tacrolimus group. The level of BUN and Cr were lower in the groups treated with a combination of tacrolimus and losartan or captopril. While ACE2 level increased in the groups receiving a combination of tacrolimus and losartan or captopril, the level of increase was insignificant, compared to the group treated with tacrolimus alone. The glomerulus diameter and the thickness of the renal proximal tubular epithelium significantly decreased in the group treated with tacrolimus alone. the mentioned variables increased in the group treated with a combination of tacrolimus and losartan or captopril, compared to the tacrolimus group.

Conclusion According to this study, tacrolimus increased the BUN and Cr levels while decreasing the ACE2 levels. However, tacrolimus in combination with losartan or captopril seemed to decrease the nephrotoxicity of the drug.

Key words

tacrolimus - losartan - captopril - nephrotoxicity - rat


Publikationsverlauf

Eingereicht: 12. Mai 2020

Angenommen: 14. Dezember 2020

Artikel online veröffentlicht:
12. März 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Scott LJ, McKeage K, Keam SJ. et al. Tacrolimus. Drugs 2003; 63: 1247-1297
    CrossrefPubMedGoogle Scholar
  • 2 Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Critical Reviews in Oncology/Hematology 2005; 56: 23-46
    CrossrefPubMedGoogle Scholar
  • 3 Tao X, Wang W, Jing F. et al. Long-term efficacy and side effects of low-dose tacrolimus for the treatment of myasthenia gravis. Neurological Sciences 2017; 38: 325-330
    CrossrefPubMedGoogle Scholar
  • 4 Kidokoro K, Satoh M, Nagasu H. et al. Tacrolimus induces glomerular injury via endothelial dysfunction caused by reactive oxygen species and inflammatory change. Kidney and Blood Pressure Research 2012; 35: 549-557
    CrossrefPubMedGoogle Scholar
  • 5 Nankivell BJ, Chapman JR, Bonovas G. et al. Oral cyclosporine but not tacrolimus reduces renal transplant blood flow. Transplantation 2004; 77: 1457-1459
    CrossrefPubMedGoogle Scholar
  • 6 Reid IA, Morris BJ, Ganong WF. The renin-angiotensin system. Annual Review of Physiology 1978; 40: 377-410
    CrossrefPubMedGoogle Scholar
  • 7 Stroth U, Unger T. The renin-angiotensin system and its receptors. Journal of Cardiovascular Pharmacology 1999; 33: S21-S28
    CrossrefPubMedGoogle Scholar
  • 8 Leung P, Sernia C. The renin-angiotensin system and male reproduction: new functions for old hormones. Journal of Molecular Endocrinology 2003; 30: 263-270
    CrossrefPubMedGoogle Scholar
  • 9 Sher Y, Maldonado JR. Psychosocial Care of End-Stage Organ Disease and Transplant Patients. Springer; 2019
    CrossrefGoogle Scholar
  • 10 Khanna AK, Pieper GM. NADPH oxidase subunits (NOX-1, p22phox, Rac-1) and tacrolimus-induced nephrotoxicity in a rat renal transplant model. Nephrology Dialysis Transplantation 2007; 22: 376-385
    CrossrefPubMedGoogle Scholar
  • 11 Ruggenenti P, Perna A, Gherardi G. et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. The Lancet 1999; 354: 359-364
    CrossrefPubMedGoogle Scholar
  • 12 Collaboration BPLTT. Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials. The Lancet 2003; 362: 1527-1535
    CrossrefPubMedGoogle Scholar
  • 13 Martin ST, Roberts KL, Malek SK. et al. Induction treatment with rabbit antithymocyte globulin versus basiliximab in renal transplant recipients with planned early steroid withdrawal. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2011; 31: 566-573
    CrossrefPubMedGoogle Scholar
  • 14 Meier-Kriesche HU, Li S, Gruessner RW. et al. Immunosuppression: evolution in practice and trends, 1994–2004. American Journal of Transplantation 2006; 6: 1111-1131
    CrossrefPubMedGoogle Scholar
  • 15 Agirbasli M, Papila-Topal N, Ogutmen B. et al. The blockade of the renin-angiotensin system reverses tacrolimus related cardiovascular toxicity at the histopathological level. Journal of the Renin-Angiotensin-Aldosterone System 2007; 8: 54-58
    CrossrefPubMedGoogle Scholar
  • 16 Haynes R, Baigent C, Harden P. et al. Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol. Transplantation Research 2013; 2: 7
    CrossrefPubMedGoogle Scholar
  • 17 Fawcett J, Scott J. A rapid and precise method for the determination of urea. Journal of Clinical Pathology 1960; 13: 156-159
    CrossrefPubMedGoogle Scholar
  • 18 Peters JH. The determination of creatinine and creatine in blood and urine with the photoelectric colorimeter. J Biol Chem 1942; 146: 11
    CrossrefPubMedGoogle Scholar
  • 19 Randhawa PS, Saad RS, Jordan M. et al. Clinical significance of renal biopsies showing concurrent acute rejection and tacrolimus-associated tubular vacuolization1. Transplantation 1999; 67: 85-89
    CrossrefPubMedGoogle Scholar
  • 20 Dunn FG, Oigman W, Ventura HO. et al. Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension. The American Journal of Cardiology 1984; 53: 105-108
    CrossrefPubMedGoogle Scholar
  • 21 Nakatani T, Uchida J, Iwai T. et al. Renin mRNA expression and renal dysfunction in tacrolimus-induced acute nephrotoxicity. International Journal of Molecular Medicine 2003; 11: 75-78
    PubMedGoogle Scholar
  • 22 Deniz H, Öğütmen B, Cakalağaoğlu F. et al. editors. Inhibition of the renin angiotensin system decreases fibrogenic cytokine expression in tacrolimus nephrotoxicity in rats. Transplantation Proceedings. 2006. Elsevier;
    CrossrefGoogle Scholar
  • 23 Hošková L, Málek I, Kautzner J. et al. Tacrolimus-induced hypertension and nephrotoxicity in Fawn-Hooded rats are attenuated by dual inhibition of renin–angiotensin system. Hypertension Research 2014; 37: 724-732
    CrossrefPubMedGoogle Scholar
  • 24 Jantz AS, Patel SJ, Suki WN. et al. Treatment of acute tacrolimus toxicity with phenytoin in solid organ transplant recipients. Case Reports in Transplantation. 2013;2013
  • 25 Mitamura T, Yamada A, Ishida H. et al. Tacrolimus (FK506)-induced nephrotoxicity in spontaneous hypertensive rats. The Journal of Toxicological Sciences 1994; 19: 219-226
    CrossrefPubMedGoogle Scholar
  • 26 Han S, Mun K, Choi H. et al. editors. Effects of Cyclosporine and Tacrolimus on the oxidative stress in Cultured Mesangial Cells. Transplantation Proceedings. 2006. Elsevier;
    CrossrefGoogle Scholar
  • 27 Liptak P, Ivanyi B. Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts. Nature clinical practice Nephrology 2006; 2: 398-404
    CrossrefPubMedGoogle Scholar
  • 28 Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clinical Journal of the American Society of Nephrology 2009; 4: 481-508
    CrossrefPubMedGoogle Scholar