Therapeutic effect of valsartan against doxorubicin-induced renal toxicity in rats

Document Type: Original Article

Authors

1 Department of Pharmacology, City College, Wuhan University of Science and Technology, Wuhan, China

2 Department of Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, China

Abstract

Objective(s): Doxorubicin (DXR)-induces glomerular atrophy and fibrosis in rat kidneys. The objective of the current study was to investigate the protective effects of valsartan on DXR-induced glomerular toxicity and its mechanisms of actions in rats.
Materials and Methods: Male Sprague-Dawley (SD) rats were divided into four groups, and each group contains ten rats. First group was control and was treated with saline only. Treatment groups were injected with DXR (6.5 mg/kg) alone, or intragastric gavage with 10 mg/kg or 20 mg/kg of valsartan after DXR treatment.
Results: Rats treated with DXR only showed significant changes in concentrations of urinary protein, serum creatinine (SCr), and blood urea nitrogen (BUN).  Moreover, glomerular structural damages were observed in rats treated with DXR.  Valsartan significantly alleviated the effect of DXR. Dramatic elevation in malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS) and significant reductions in the levels of reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) were seen after DXR treatment. These effects were effectively ameliorated by co-administration with valsartan.
Conclusion: The findings of our study indicate that valsartan may play an important role in protecting DXR-induced renal toxicity, at least in part, through its antioxidant properties.

Keywords

Main Subjects


1. Saad SY, Najjar TA, Al-Rýkabý AC, et al. The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol Res 2001; 43: 211–218.
2. Liu LL, Li QX, Lin Xia, Li J, Shao L.  Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Toxicology 2007; 231:81–90.
3. Criscione L, Gasparo M, Bühlmayer P, Whitebread S, Ramjoué HP, Wood J. Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol 1993; 110:761–771.
4. Müller P, Cohen T, Gasparo M, Sioufi A, RacinePA, Howald H, et al.  Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects. Eur J Clin Pharmacol 1994; 47:231–245.
5. Wang Y, Wei RB, Yang Y, Su TY, Huang MJ, Li P, Chen XM, et al.  Valsartan alleviates insulin resistance in skeletal muscle of chronic renal failure rats. Med Sci Monit 2018; 24:2413–2419.
6. Wu K, Zhou T, Sun G, Wang W, Zhang Y, et al. Valsartan inhibited the accumulation of dendritic cells
in rat fibrotic renal tissue. Cellular & Molecular Immunology 2006; 3:213–220.
7. Raeisi S,  Ghorbanihaghjo A,  Argani H,  Dastmalchi S, Ghasemi B, et al.  The effects of valsartan on renal glutathione peroxidase expression in alleviation of cyclosporine nephrotoxicity in rats. Bioimpacts Bi 2016; 6:119–124.
8. Gervasini G, Robles N R. Potential beneficial effects of sacubitril-valsartan in renal disease: a new field for a new drug. Expert Opinion on Investigational Drugs 2017; 26:651–659.
9. Salant DJ, Ybulsky AV. Experimental glomerulonephritis. Meth Enzymol 1988; 162:421–461.
10. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95:351–358.
11. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autooxidation of pyrogallol and convenient assay for superoxide dismutase. Eur J Biochem 1974; 47:469–474.
12. Beutler E, Durom O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963; 61: 882–888.
13. Flohe L, Gunzler WA. Assays of glutathione peroxidase. Methods Enzymol 1984; 105:114–121.
14. Stuehr DJ, Know NS, Gross SS. Synthesis of nitrogen oxides from l-arginine by macrophage cytosol: requirement for inducible and constitutive components. Biochem Biophys Res Commun 1989; 161:420–426.
15. Lowry OH, Rosebrough NJ, Far AL, Randall RJ. Protein measurement with Folin phenol reagent. J Biol Chem 1951; 193:265–275.
16. Luis MR, Jean CA, Claudio P, Pascale OS, Florence B, Johannes F M, et al.  Safety of the combination of valsartan and benazepril in patients with chronic renal disease. J Hypertens 2000; 18:89–95.
17. Sun Y, Peng PA, Ma Y. Valsartan protects against contrast-induced acute kidney injury in rats by inhibiting endoplasmic reticulum stress-induced apoptosis. Curr Vasc Pharmacol 2017; 15:174–183.
18. Wu K, Zhou T, Sun G, Wang W, Zhang Y, et al.  Valsartan inhibited the accumulation of dendritic cells in rat fibrotic renal tissue. Cell Mol Immunol 2006; 3:213-220.
19. De BEL, Bottone AE, Voest, EE. Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. Eur J Pharmacol 2001; 415:1–11.
20. Singal PK, Li T, Kumar D, Danelisen I, Iliskovic N. Adriamycin-induced heart failure: mechanism and modulation. Mol Cell Biochem 2000; 207:77–86.
21. Fujihara CK, Sena CR, Malheiros DM, Mattar AL, Zatz R. Shortterm nitric oxide inhibition induces progressive nephropathy after regression of initial renal injury. Am J Physiol Renal Physiol 2006; 290:632–640.
22. Passauer J, Pistrosch F, Bussemaker E. Nitric oxide in chronic renal failure. Kidney Int 2005; 67:1665–1667.
23. Dobashi K, Ghosh B, Orak JK, Singh I, Singh AK. Kidney ischemia-reperfusion: modulation of antioxidant defenses. Mol Cell Biochem 2000; 205:1-11.