Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis
Abstract
:1. Introduction
2. Results
2.1. Effect on Body, Relative Kidney Weight, and Renal Function Parameters
2.2. Effect of ADM on Redox and Inflammatory Status
2.3. Effect of ADM on Inflammasome Protein and Pyroptosis Markers in Renal Tissues
2.4. DNA Ladder Assay
2.5. Effect of ADM on Renal Cortex Histological Features
2.6. Effect of ADM on Bax Immunohistochemical Staining
2.7. Effect of ADM on Bcl-2 Immunohistochemical Staining
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Chemicals and Drugs
4.3. Experimental Design
4.4. Collection of Urine Samples
4.5. Blood and Tissue Sampling
4.6. Determination of Relative Kidney Weight
4.7. Evaluation of Nephrotoxicity
4.8. Renal Redox Status and Inflammatory Markers
4.9. Assessment of Inflammasome Activation and Pyroptosis in Renal Tissues
4.10. Determination of DNA Fragmentation by Ladder Assay
4.11. Real-Time Quantitative PCR (qPCR)
4.12. Pyroptosis Protein Expression by Western Blotting
4.13. Immunohistochemical Analysis of the Kidney
4.14. Histopathological Examination of the Kidney
4.15. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Parameter/Group | Group I (Control) | Group II (DOX) | Group III (ADM + DOX) | Group IV (ADM) |
---|---|---|---|---|
Initial body weight (g) | 163.86 ± 8.07 | 165.57 ± 13.04 | 166.29 ± 12.19 | 163.43 ± 6.97 |
Final body weight (g) | 190.28 ± 5.31 Δ | 153.29 ± 12.27 * | 156.57 ± 11.86 * | 188 ± 6.08 Δ |
Relative kidney weight (%) | 0.29 ± 0.02 Δ | 0.52 ± 0.07* | 0.50 ± 0.04 * | 0.28 ± 0.01 Δ |
Serum creatinine level (mg/dL) | 0.48 ± 0.04 Δ | 0.89 ± 0.02 * | 0.67 ± 0.02 *,Δ | 0.50 ± 0.03 Δ |
BUN (mg/dL) | 27.51 ± 0.31 Δ | 42.55 ± 0.67 * | 30.61 ± 0.45 *,Δ | 27.76 ± 0.43 Δ |
Creatinine clearance (mL/min) | 1.68 ± 0.10 Δ | 0.23 ± 0.04 * | 0.41 ± 0.05 *,Δ | 1.63 ± 0.09 Δ |
Urinary KIM-1(ng/mL) | 6.25 ± 0.91 Δ | 15.40 ± 2.95 * | 9.38 ± 0.90 *,Δ | 6.79 ± 0.75 Δ |
Parameter/Group | Group I (Control) | Group II (DOX) | Group III (ADM + DOX) | Group IV (ADM) |
---|---|---|---|---|
Renal MDA level (nmol/mg protein) | 1.21 ± 0.23 Δ | 3.94 ± 0.34 * | 2.35 ± 0.36 *,Δ | 1.08 ± 0.28 Δ |
Renal CAT activity (μmol of H2O2 consumed /min/mg protein) | 217.35 ± 6.88 Δ | 170.39 ± 5.27 * | 200.03 ± 1.20 *,Δ | 219.57 ± 7.48 Δ |
Renal GSH level (μmol/mg protein) | 5.24 ± 1.01 Δ | 1.21 ± 0.05 * | 5.06 ± 0.79 Δ | 4.88 ± 0.98 Δ |
Renal 8-OHdG level (ng/mg protein) | 81.77 ± 4.78 Δ | 107.30 ± 2.96 * | 100.53 ± 4.53 *,Δ | 82.86 ± 4.84 Δ |
Renal TNF-α level (pg/mg protein) | 13.95 ± 1.29 Δ | 81.75 ± 6.79 * | 45.47 ± 3.49 *,Δ | 11.86 ± 1.06 Δ |
Parameter/Group | Group I (Control) | Group II (DOX) | Group III (ADM + DOX) | Group IV (ADM) |
---|---|---|---|---|
Renal NLRP3 level (pg/mg protein) | 11.92 ± 0.96 Δ | 67.55 ± 9.53 * | 28.21 ± 1.40 *,Δ | 10.89 ± 1.07 Δ |
Renal IL-1β level (pg/mg protein) | 42.09 ± 6.07 Δ | 116.69 ± 26.13 * | 93.08 ± 14.47 *,Δ | 42.50 ± 9.61 Δ |
Renal IL-18 level (pg/mg protein) | 13.47 ± 1.93 Δ | 34.42 ± 4.79 * | 22.13 ± 2.89 *,Δ | 14.46 ± 1.65 Δ |
Parameter/Group | Group I (Control) | Group II (DOX) | Group III (ADM + DOX) | Group IV (ADM) | |
---|---|---|---|---|---|
Histopathologic score | Median | 1.0 | 2.5 | 1.0 | 1.0 |
IQR | 0.00–1.0 | 2.0–3.0 | 1.0–2.0 | 0.00–1.0 | |
Mean rank | 13.40 Δ | 33.70 * | 20.10 Δ | 14.80 Δ | |
Bcl2 immune reactivity | Mean area percentage | 45.78 ± 6.58 Δ | 19.45 ± 6.64 * | 40.59 ± 5.14 Δ | 45.85 ± 5.43 Δ |
Color intensity | 11.67 ± 1.76 Δ | 2.94 ± 1.82 * | 10.05 ± 1.86 Δ | 12.08 ± 1.50 Δ | |
Bax Immune reactivity | Mean area percentage | 21.83 ± 2.55 Δ | 37.24 ± 4.82 * | 24.11 ± 2.98 Δ | 19.14 ± 4.88 Δ |
Color intensity | 11.18 ± 1.90 Δ | 33.59 ± 6.11 * | 13.69 ± 2.03 Δ | 11.54 ± 2.12 Δ |
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Abd-Ellatif, R.N.; Nasef, N.A.; El-Horany, H.E.-S.; Emam, M.N.; Younis, R.L.; El Gheit, R.E.A.; Elseady, W.; Radwan, D.A.; Hafez, Y.M.; Eissa, A.; et al. Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis. Int. J. Mol. Sci. 2022, 23, 14570. https://doi.org/10.3390/ijms232314570
Abd-Ellatif RN, Nasef NA, El-Horany HE-S, Emam MN, Younis RL, El Gheit REA, Elseady W, Radwan DA, Hafez YM, Eissa A, et al. Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis. International Journal of Molecular Sciences. 2022; 23(23):14570. https://doi.org/10.3390/ijms232314570
Chicago/Turabian StyleAbd-Ellatif, Rania Nagi, Nahla Anas Nasef, Hemat El-Sayed El-Horany, Marwa Nagy Emam, Reham Lotfy Younis, Rehab E. Abo El Gheit, Walaa Elseady, Doaa A. Radwan, Yasser Mostafa Hafez, Ahmad Eissa, and et al. 2022. "Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis" International Journal of Molecular Sciences 23, no. 23: 14570. https://doi.org/10.3390/ijms232314570