Abstract
Nephrotoxicity is the most common adverse effect of gentamicin (GNT). This study aimed to investigate the possible nephroprotective effect of umbelliferone (UMB), against GNT-induced nephrotoxicity. Rats were allocated into the control group; UMB group (50 mg/kg/day, P.O. for 15 days); GNT group (100 mg/kg/day, i.p., for 8 days); and GNT + UMB group. By the end of the experimental period, serum creatinine, urea, and uric acid as well as urine KIM-1 and urine albumin/creatinine ratio were evaluated to estimate kidney function. Moreover, tissue samples were collected for assessment of ERK1/2, p-ERK1/2, TLR-4, p38 MAPK, NF-κB-p65, NLRP-3, IkBα, TNF-α, IL-1β, JAK1, STAT-3, p-STAT, and cleaved caspase-3. In support, the histopathological examination of renal tissues was performed. UMB improves kidney function through regulation of renal serum biomarkers, with alleviations of histological abrasions induced by GNT. Besides, UMB downregulates renal protein expressions of ERK1/ERK2, TLR-4, and p38MAPK, with subsequent suppression of NF-κB-p65/NLRP-3 inflammasome and JAK1/STAT-3 pathways as well as cleaved caspase-3. In parallel, UMB induced IkBα upregulation. Collectively, UMB markedly amended all GNT-induced renal changes. These nephroprotective outcomes could be attributed to its ability to impede TLR-4/NF-κB-p65/NLRP-3 inflammasome and JAK1/STAT-3 pathways activation, as well as to its anti-inflammatory property.
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Abbreviations
- CMC:
-
Carboxymethyl cellulose
- ERK:
-
Extracellular signal-regulated protein kinases
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- GNT:
-
Gentamicin
- IkBα:
-
Nuclear factor of kappa light polypeptide gene enhancer in B cell inhibitor-alpha
- IL-1β:
-
Interleukin-1 beta
- JAK:
-
Janus kinase
- KIM-1:
-
Kidney injury molecule-1
- NF-κB-p65:
-
Nuclear factor-kappa B-p65
- NLRP-3:
-
Nucleotide-binding domain (NOD)-like receptor protein-3
- P38 MAPK:
-
p38 mitogen-activated protein kinase
- STAT-3:
-
Signal transducers and activators of transcription-3
- TLRs:
-
Toll-like receptors
- TNF-α:
-
Tumor necrosis factor-alpha
- UMB:
-
Umbelliferone
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The authors are greatly indebted to Dr. Mohamed Abdelrazik, Lecturer of Veterinary Cytology & Histology, Faculty of Veterinary Medicine, Cairo University, Egypt, for his kind help in the histopathological investigations.
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Conception and experimental design: FEMA and EHMH. Statistical analysis: MRK. Writing of the manuscript: EHMH and OAMA. The final version of the manuscript has been approved by all authors.
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This study was approved by the Ethics Committee of the Faculty of Medicine, Assiut University (No. IRB17300463), and followed the guidelines for the care and use of laboratory animals declared by the National Institutes of Health Guide and Laboratory Animals Use (NIH Publications No. 8023, revised 1978).
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Hassanein, E.H.M., Ali, F.E.M., Kozman, M.R. et al. Umbelliferone attenuates gentamicin-induced renal toxicity by suppression of TLR-4/NF-κB-p65/NLRP-3 and JAK1/STAT-3 signaling pathways. Environ Sci Pollut Res 28, 11558–11571 (2021). https://doi.org/10.1007/s11356-020-11416-5
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DOI: https://doi.org/10.1007/s11356-020-11416-5