Effect of alpha-linolenic acid on aminoglycoside nephrotoxicity and RhoA/Rho-kinase pathway in kidney
Percin Pazarci1, Serkan Özler2, Halil Mahir Kaplan3
1Department of Medical Biology, Cukurova University Faculty of Medicine, Adana, Turkey.
Abstract:
Aminoglycoside nephrotoxicity stands as a primary contributor to the development of acute intrinsic renal failure. Distinctive characteristic associated with this nephrotoxicity is the occurrence of tubular necrosis, which is why it is commonly referred to as acute tubular necrosis. Studies have demonstrated that inhibiting rhoA/rho-kinase pathway is beneficial for kidney damage induced by diabetes and renal ischemia. Comparable pathological conditions can be observed in aminoglycoside nephrotoxicity, like those found in diabetes and renal ischemia. Gentamicin, an aminoglycoside, is known to activate Rho/Rho-kinase pathway. The primary goal of this study is to explore influence of oxidative stress on this pathway by concurrently administering gentamicin and alpha-linolenic acid (ALA) possessing known antioxidant properties. To achieve this, gentamicin (100 mg kg-1) and ALA (70 mg kg-1) were administered to mice for a period of 9 days, and Rho/Rho-kinase pathway was examined by using ELISA. Administration of gentamicin to mice led to an elevation in RhoA and rho-kinase II levels, along with the activity of rho-kinase in kidneys. However, ALA effectively reversed this heightened response. ALA, known for its antioxidant properties, inhibited activation of Rho/Rho-kinase pathway induced by gentamicin. This finding suggests that gentamicin induces nephrotoxicity through oxidative stress.
Insights
Alpha-linolenic acid (ALA) reverses gentamicin-induced kidney damage by inhibiting the Rho/Rho-kinase pathway. This suggests gentamicin causes nephrotoxicity via oxidative stress, and ALA offers a potential protective effect.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Aminoglycoside nephrotoxicity is a major cause of acute kidney injury, characterized by tubular necrosis.
- The Rho/Rho-kinase pathway is implicated in kidney damage from diabetes and ischemia, conditions sharing pathological similarities with aminoglycoside nephrotoxicity.
- Gentamicin, an aminoglycoside antibiotic, activates the Rho/Rho-kinase pathway.
Purpose of the Study:
- To investigate the role of oxidative stress in aminoglycoside nephrotoxicity.
- To determine if alpha-linolenic acid (ALA), an antioxidant, can mitigate gentamicin-induced kidney damage by modulating the Rho/Rho-kinase pathway.
Main Methods:
- Mice were administered gentamicin (100 mg/kg) and ALA (70 mg/kg) daily for 9 days.
- Kidney tissues were analyzed using ELISA to measure RhoA and rho-kinase II levels and rho-kinase activity.
Main Results:
- Gentamicin administration significantly increased RhoA and rho-kinase II levels and rho-kinase activity in mouse kidneys.
- Concurrent administration of ALA effectively reversed these gentamicin-induced elevations.
- ALA demonstrated an inhibitory effect on the gentamicin-induced activation of the Rho/Rho-kinase pathway.
Conclusions:
- Gentamicin induces nephrotoxicity, at least partially, through oxidative stress mechanisms that activate the Rho/Rho-kinase pathway.
- Alpha-linolenic acid exhibits protective effects against gentamicin-induced nephrotoxicity by inhibiting this pathway, highlighting its potential therapeutic value.
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