Methotrexate-Induced Alteration of Renal Aquaporins 1 and 2, Oxidative Stress and Tubular Apoptosis Can Be Attenuated by Omega-3 Fatty Acids Supplementation

Abstract

Methotrexate (MTX) is a potent anti-cancer drug, commonly associated with nephrotoxicity via the induction of oxidative stress and apoptosis with alteration of renal water channel proteins, namely aquaporins (AQPs). Omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) have shown cytoprotective effects through their anti-oxidant and antiapoptotic activities. The present study aims for the first time to explore the role of LC-PUFA against MTX-induced nephrotoxicity. Rats were divided into the following groups: saline control, LC-PUFA control, MTX, MTX + LC-PUFA (150 mg/kg), or MTX + LC-PUFA (300 mg/kg). Then, H&E staining and immunohistochemical staining for the anti-apoptosis marker B-cell lymphoma 2 (BCL-2), the apoptosis marker BCL2-Associated X Protein (BAX), the proinflammatory marker Nuclear factor kappa B (NF-kB), AQPs 1 and 2 were performed in kidney sections with an assessment of renal oxidative stress. The MTX caused a renal histopathological alteration, upregulated renal BAX and NF-kB, downregulated Bcl-2 and AQP1, altered the distribution of AQP2, and caused oxidative stress. The LC-PUFA attenuated the pathological changes and decreased renal BAX and NF-kB, increased BCL-2 and AQP1, restored the normal distribution of AQP2, and decreased the oxidative stress. Therefore, LC-PUFA is a good adjuvant to MTX to prevent its adverse effects on kidneys through its antiapoptotic, antioxidant, and anti-inflammatory effect and its role in the restoration of the expression of AQPs 1 and 2.

Platelet Rich Plasma and Adipose-Derived Mesenchymal Stem Cells Mitigate Methotrexate-Induced Nephrotoxicity in Rat via Nrf2/Pparγ/HO-1 and NF-Κb/Keap1/Caspase-3 Signaling Pathways: Oxidative Stress and Apoptosis Interplay

“…In addition, it causes glomerulosclerosis with widening of Bowman’s space in many glomeruli. Such methotrexate-induced toxic effects in renal tubules and glomeruli have been observed in previous research [ 90 , 91 , 92 , 93 ]. MTX causes renal injury by increasing the formation of reactive oxygen species, which results in oxidative stress.…”

Quillaja saponin mitigates methotrexate-provoked renal injury; insight into Nrf-2/Keap-1 pathway modulation with suppression of oxidative stress and inflammation

“…As a classical folate antagonist, MTX is also used in cancer treatment to induce apoptosis in cancer cells. Unfortunately, MTX has the potential to influence cancer cells and normal cells [ 7 ]. Therefore, MTX utilization is associated with serious toxic outcomes on several organs, making its clinical use is evidently confined [ 42 ].…”

“…Therefore, MTX utilization is associated with serious toxic outcomes on several organs, making its clinical use is evidently confined [ 42 ]. Owing to the fact that MTX is predominantly excreted by the kidneys by glomerular filtration and active transport, nephrotoxicity represents a common adverse effect [ 7 ]. MTX-induced nephrotoxicity occurs when MTX and its metabolites crystallize and precipitate within the renal tubular lumens, along with direct toxicity on mesangial- or tubular epithelial cells, as a result of MTX-enhanced OS and inflammation [ 40 ].…”

“…There are multiple mechanisms of MTX-mediated kidney toxicity, including allergic interstitial nephritis, direct pharmacological toxicity, and precipitation of MTX in renal tubules, which plugs the tubular lumens [ 6 ]. MTX-induced nephrotoxicity is commonly induced as a consequence of oxidative stress, suppression of DNA production, inflammatory infiltration, and apoptosis [ 7 ]. Under homeostatic circumstances, cells keep the redox microenvironment at a higher reducing power.…”

Rheumatoid arthritis and the risk of end-stage renal disease: A nationwide, population-based study

“…In addition, protective and prophylactic measures, such as administration of nephroprotective agents including safe antioxidants and anti-inflammatory agents as supplementation, to decrease the incidence of ESRD among RA patients should also be established. For instance, omega-3 fatty acid attenuated methotrexate-induced nephrotoxicity in a pre-clinical trial ( 32 ), although it is necessary to further validate whether the use of omega-3 fatty acid lowers the risk of ESRD in patients with RA. In this context, it is worthy of note that Hagar et al reported that the introduction of pharmaceutical care services in RA patient treatment protocol effectively resulted in an improvement in the detection and prevention of drug-related problems and showed a significant reduction in Disease Activity Score 28, Health Assessment Questionnaire, and Rheumatoid Arthritis Quality of Life Questionnaire scores ( 33 ).…”