Xanthenone, ACE2 activator, counteracted gentamicin-induced nephrotoxicity in rats: Impact on oxidative stress and ACE2/Ang-(1–7) signaling

Nephrotoxicity is a rapid deterioration of kidney function due to exposure to nephrotoxic drugs as gentamicin. Gentamicin increases the generation of reactive oxygen species (ROS) leading to inflammatory responses and nuclear factor-κB (NF-κB) activation. The renal renin-angiotensin system (RAS) is...

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Bibliographic Details
Published in:Life sciences (1973) 2021-06, Vol.275, p.119387, Article 119387
Main Authors: Abdel-Fattah, Maha M., Elgendy, Abdel Nasser.A.M., Mohamed, Wafaa R.
Format: Article
Language:English
Subjects:
ACE2
ACE2 activator
Acute Kidney Injury - chemically induced
Acute Kidney Injury - prevention & control
Ang-(1–7)
Angiotensin
Angiotensin I - metabolism
Angiotensin II
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - drug effects
Angiotensin-Converting Enzyme 2 - metabolism
Animals
Antioxidants
Blotting, Western
Creatinine
Gentamicin
Gentamicins - toxicity
Glutathione
Homeostasis
Inflammation
Interleukin 6
Interleukins - metabolism
Kidneys
Male
Malondialdehyde
Nephrotoxicity
NF-κB protein
Oxidative stress
Oxidative Stress - drug effects
Peptide Fragments - metabolism
Peptidyl-dipeptidase A
Rats
Rats, Wistar
Reactive oxygen species
Renin
Serum levels
Signal Transduction - drug effects
Superoxide dismutase
Tumor necrosis factor-TNF
Tumor necrosis factor-α
Urea
Xanthenone
Xanthones - pharmacology
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Summary:Nephrotoxicity is a rapid deterioration of kidney function due to exposure to nephrotoxic drugs as gentamicin. Gentamicin increases the generation of reactive oxygen species (ROS) leading to inflammatory responses and nuclear factor-κB (NF-κB) activation. The renal renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression through the classic ACE/Ang-II/AT1 axis and its antagonist, ACE2/Ang-(1–7)/Mas axis which exerts an important role in the kidney. The present study evaluates the protective effects of the angiotensin-converting enzyme 2 (ACE2) activator; xanthenone; against experimental nephrotoxicity induced by gentamicin. Rats were divided into 4 groups, normal control, xanthenone (2 mg/kg, s.c), gentamicin (100 mg/kg, i.p. for one week) and xanthenone + gentamicin groups. Blood urea nitrogen (BUN) and serum creatinine levels were measured. The kidney tissues were used for estimating glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), NF-κB, Angiotensin II (AngII), and Ang-(1–7). In addition, histopathological examination and Western blot analysis of ACE2 expression were done. Xanthenone significantly restored serum levels of BUN and creatinine. Xanthenone exerted significant antioxidant effect as revealed by increased GSH content and SOD activity together with reduced MDA content. It exerted anti-inflammatory effect by significant reduction in TNF-α, NF-κB and IL-6 expression compared to gentamicin group. Xanthenone increased Ang-(1–7) and ACE2 expression while significantly decreased Ang-II expression. Histopathologically, xanthenone markedly counteracted gentamicin-induced renal aberrations. Activation of ACE2/Ang-(1–7) by xanthenone produced significant antioxidant and anti-inflammatory effects that counteracted gentamicin-induced nephrotoxicity. [Display omitted]
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2021.119387