Umbelliferone attenuates gentamicin-induced renal toxicity by suppression of TLR-4/NF-κB-p65/NLRP-3 and JAK1/STAT-3 signaling pathways

• Published in: Environmental science and pollution research international 2021-03, Vol.28 (9), p.11558-11571
• Main Authors: Hassanein, Emad H. M., Ali, Fares E. M., Kozman, Magy R., Abd El-Ghafar, Omnia A. M.
• Format: Article
• Language: English
• Subjects: adverse effects; Albumins; Animals; anti-inflammatory activity; Anti-inflammatory agents; Aquatic Pollution; Atmospheric Protection/Air Quality Control/Air Pollution; Biomarkers; blood serum; Caspase-3; Creatinine; Earth and Environmental Science; Ecotoxicology; Environment; Environmental Chemistry; Environmental Health; Environmental science; Gentamicin; Gentamicins - toxicity; histology; histopathology; IL-1β; Inflammasomes; Inflammation; Janus kinase; Kidney - metabolism; Kidneys; MAP kinase; mitogen-activated protein kinase; nephroprotective effect; nephrotoxicity; NF-kappa B - metabolism; NF-κB protein; Rats; Renal function; Research Article; Signal Transduction; Stat3 protein; Toll-Like Receptor 4; Toxicity; Tumor necrosis factor-α; Umbelliferone; umbelliferones; Umbelliferones - pharmacology; Urea; Uric acid; urine; Waste Water Technology; Water Management; Water Pollution Control
• ISSN: 0944-1344; 1614-7499
• DOI: 10.1007/s11356-020-11416-5

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.