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PARP inhibition ameliorates nephropathy in an animal model of type 2 diabetes: focus on oxidative stress, inflammation, and fibrosis

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Abstract

Poly(ADP-ribose) polymerase (PARP) enzyme contributes to nephropathy, a serious diabetic complication which may lead to end-stage renal disease. The study aims to investigate the effect of PARP over-activation on kidney functions in a type 2 diabetic rat model. The study also tests the therapeutic use of PARP inhibitors in diabetic nephropathy. Type 2 diabetes was induced in adult male rats by high-fructose/high-fat diet and low streptozotocin dose. Then, the PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for 10 weeks. At the end, urine samples were collected to measure urine creatinine, albumin, and total proteins. PARP activity, superoxide dismutase (SOD) activity, and nitrite content were measured in kidney tissue homogenate. Glucose, fructosamine, insulin, and tumor necrosis factor-alpha (TNF-α) were measured in serum. Furthermore, histological studies, collagen deposition, and immunofluorescence of nuclear factor kappa B (NFκB) and transforming growth factor beta1 (TGF-β1) were carried out. PARP enzyme activity was significantly higher in the diabetic group and was significantly reduced by 4-AB administration. Diabetic animals had clear nephropathy indicated by proteinuria and increased albumin excretion rate (AER) which were significantly decreased by PARP inhibition. In addition, PARP inhibition increased creatinine clearance in diabetic animals and reduced renal TGF-β1 and glomerular fibrosis. Moreover, PARP inhibition alleviated the elevated serum TNF-α level, renal NFκB, nitrite, and the decrease in SOD activity in diabetic animals. However, PARP inhibition did not significantly affect neither hyperglycemia nor insulin sensitivity. PARP enzyme inhibition alleviates diabetic nephropathy through decreasing inflammation, oxidative stress, and renal fibrosis.

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Acknowledgments

This work was funded by a research fund from the Egyptian Ministry for Higher Education Funding Agency; Science and Technology Development (STDF, www.stdf.org.eg), Fund ID 1024.

Authors’ contributions statement

EMZ carried out laboratory experiments, animal handling procedures, data and statistical analysis, collected field data, and participated in drafting the manuscript; HME-B raised the idea, designed the experiments, and participated in statistical analysis and revising the manuscript; NNE-M participated in the study conception, design, and coordination; AAA carried out histological examination; and AFA participated in study coordination. All authors gave final approval for publication.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, Zagazig University, P.O. Box 44519, Zagazig, Egypt

    Esraa M. Zakaria, Ahmed F. Ahmed & Hany M. El-Bassossy

  2. Department of Pharmacology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), Cairo, Egypt

    Nabila N. El-Maraghy

  3. Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt

    Abdelmonim A. Ali

  4. Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Hany M. El-Bassossy

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  1. Esraa M. Zakaria
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  2. Nabila N. El-Maraghy
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  3. Ahmed F. Ahmed
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  4. Abdelmonim A. Ali
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Correspondence to Esraa M. Zakaria.

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Funding

This work was funded by a research fund from the Egyptian Ministry for Higher Education Funding Agency; Science and Technology Development (STDF, www.stdf.org.eg), Fund ID 1024.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experimental procedures were performed in accordance with the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978).

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Zakaria, E.M., El-Maraghy, N.N., Ahmed, A.F. et al. PARP inhibition ameliorates nephropathy in an animal model of type 2 diabetes: focus on oxidative stress, inflammation, and fibrosis. Naunyn-Schmiedeberg's Arch Pharmacol 390, 621–631 (2017). https://doi.org/10.1007/s00210-017-1360-9

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