Pre-treatment with 2-mercaptoethanol attenuates ferroptosis-associated redox imbalance and inflammatory responses, but not tubulointerstitial fibrosis, in unilateral ureteral obstruction.
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Abstract
Background: Unilateral ureteral obstruction (UUO) induces oxidative stress, inflammation, ferroptosis, and progressive fibrotic remodeling. Whether pharmacological modulation of ferroptosis-related redox imbalance attenuates obstructive kidney injury remains unclear. In this study, we investigated the effects of the thiol-containing antioxidant 2-mercaptoethanol (2-ME) in a mouse UUO model.
Methods: Mice subjected to UUO received either pre-treatment or delayed treatment with 2-ME. Ferroptosis-related markers, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), the ratio of reduced to oxidized glutathione (GSH/GSSG), and lipid hydroperoxides, as well as inflammatory mediators, F4/80-positive macrophage infiltration, Havcr1 mRNA expression, and fibrotic parameters were evaluated using molecular and histological analyses.
Results: UUO markedly decreased the expression of GPX4 and SLC7A11, reduced the GSH/GSSG ratio, and elevated lipid hydroperoxide levels. These changes were accompanied by increased tubular injury scores, infiltration of F4/80-positive macrophages, and extracellular matrix accumulation. Pre-treatment with 2-ME increased GPX4 and SLC7A11 expression, improved the GSH/GSSG balance, reduced lipid hydroperoxide levels, and attenuated inflammatory activation. Additionally, 2-ME pre-treatment significantly reduced tubular injury scores and Havcr1 mRNA expression. However, 2-ME did not consistently suppress collagen deposition or the expression of fibrosis-related genes. Delayed administration of 2-ME failed to significantly alter antioxidant, inflammatory, or fibrotic markers.
Conclusions: Pre-treatment with 2-ME attenuates ferroptosis-associated redox imbalance and inflammatory responses in UUO but does not consistently suppress tubulointerstitial fibrosis. These findings suggest that 2-ME can serve as a pharmacological tool to modulate thiol-dependent redox balance and inflammatory activation during UUO, whereas fibrosis progression likely involves additional mechanisms.
期刊介绍：
Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures.
Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology.
Studies of plant extracts are not suitable for Pharmacological Reports.
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