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Effect of tocilizumab, an interleukin-6 inhibitor, on early stage streptozotocin-induced diabetic nephropathy in rats

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Abstract

The aim of this study was to examine the effect of tocilizumab, an interleukin-6 (IL-6) inhibitor on streptozotocin-induced diabetic nephropathy. Male Sprague-Dawley rats (n = 36) were distributed into six groups and treated for 4 weeks. Groups 1, 3, 5 received either saline, tocilizumab (2 mg/kg), or tocilizumab (8 mg/kg) injection intraperitoneally (i.p.), every 2 weeks, respectively. Groups 2, 4, 6 were rendered diabetic by a single i.p. injection of streptozotocin (65 mg/kg) and were treated as in groups 1, 3, 5, respectively. Biochemical parameters were measured in plasma, urine, and kidneys. In the untreated diabetic group, there was a significant decrease in body weight, polyuria, and increased kidney weight. There was increased urinary albumin/creatinine ratio (UACR) and N-acetyl-β-D-glucosaminidase (NAG)/creatinine ratio (UNCR). Streptozotocin also induced a significant increase in creatinine clearance. In addition, diabetes was associated with increased oxidative stress [reduced renal glutathione reductase (GR), superoxide dismutase (SOD), catalase activities, and increased malondialdhyde (MDA)] and increased plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) concentrations. Kidneys from streptozotocin-treated rats showed marked vacuolation of the proximal tubular epithelium with focal tubular necrosis and the glomeruli showing increase in mesangial cells. Tocilizumab significantly mitigated the increase in UACR and UNCR, renal MDA, plasma TNF-α, IL-6 and NO levels, and the decrease in renal SOD and catalase activities in diabetic rats. Tocilizumab did not significantly improve creatinine clearance; however, it attenuated the histopathological changes induced by streptozotocin. This study shows that tocilizumab was able to ameliorate some of the changes seen in streptozotocin-induced early diabetic nephropathy in rats. This is mainly due to its anti-inflammatory and antioxidative effects.

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Funding

Supported by a grant from Sultan Qaboos University (IG/MED//PHAR/16/02).

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Authors and Affiliations

  1. Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, PO Box 35, Al-Khod, 123, Sultanate of Oman

    Aly M. Abdelrahman, Yousuf Al Suleimani, Mohammed Ashique, Priyadarsini Manoj & Badreldin H. Ali

  2. Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, PO Box 35, Al-Khod, Oman

    Asem Shalaby

  3. Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Asem Shalaby

Authors
  1. Aly M. Abdelrahman
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  2. Yousuf Al Suleimani
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  3. Asem Shalaby
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  4. Mohammed Ashique
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  5. Priyadarsini Manoj
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  6. Badreldin H. Ali
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Contributions

A.A.; Y.S.; B.A.: conceived and designed research, participated in the interpretation of the results, writing and review of the manuscript.

A.S.: conducted histopathology.

M.A.; P.M.: conducted the experiments and analysis of data.

Corresponding author

Correspondence to Aly M. Abdelrahman.

Ethics declarations

All experimental designs were approved by the Medical Research Committee, College of Medicine and Health Sciences, Sultan Qaboos University. All procedures involving animals and their care were carried out in accordance with the guidelines of the Animal Ethical Committee of Sultan Qaboos University and international laws and policies (EEC Council directives 2010/63/EU, 22 September, 2010 and NIH Guide for the Care and Use of Laboratory Animals, NIH Publications, 8th edition, 2011).

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The authors declare that they have no conflict of interests.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Abdelrahman, A.M., Al Suleimani, Y., Shalaby, A. et al. Effect of tocilizumab, an interleukin-6 inhibitor, on early stage streptozotocin-induced diabetic nephropathy in rats. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1005–1013 (2019). https://doi.org/10.1007/s00210-019-01655-w

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  • DOI: https://doi.org/10.1007/s00210-019-01655-w

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