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Diosmin Mitigates Gentamicin-Induced Nephrotoxicity in Rats: Insights on miR-21 and -155 Expression, Nrf2/HO-1 and
Rania I Nadeem1, Amany S Aboutaleb2, Nancy S Younis3
1Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
Abstract:
Gentamicin (GNT) is the most frequently used aminoglycoside. However, its therapeutic efficacy is limited due to nephrotoxicity. Thus, the potential anticipatory effect of Diosmin (DIOS) against GNT-prompted kidney damage in rats together with the putative nephroprotective pathways were scrutinized. Four groups of rats were used: (1) control; (2) GNT only; (3) GNT plus DIOS; and (4) DIOS only. Nephrotoxicity was elucidated, and the microRNA-21 (miR-21) and microRNA-155 (miR-155) expression and Nrf2/HO-1 and p38-MAPK/NF-κB pathways were assessed. GNT provoked an upsurge in the relative kidney weight and serum level of urea, creatinine, and KIM-1. The MDA level was markedly boosted, with a decline in the level of TAC, SOD, HO-1, and Nrf2 expression in the renal tissue. Additionally, GNT exhibited a notable amplification in TNF-α, IL-1β, NF-κB p65, and p38-MAPK kidney levels. Moreover, caspase-3 and BAX expression were elevated, whereas the Bcl-2 level was reduced. Furthermore, GNT resulted in the down-regulation of miR-21 expression along with an up-regulation of the miR-155 expression. Histological examination revealed inflammation, degradation, and necrosis. GNT-provoked pathological abnormalities were reversed by DIOS treatment, which restored normal kidney architecture. Hence, regulating miR-21 and -155 expression and modulating Nrf2/HO-1 and p38-MAPK/NF-κB pathways could take a vital part in mediating the reno-protective effect of DIOS.
Insights
Diosmin (DIOS) protects against gentamicin (GNT)-induced kidney damage in rats. This study investigated DIOS’s protective mechanisms involving microRNA and key cellular pathways.
Area of Science:
- Pharmacology and Toxicology
- Nephrology
- Molecular Biology
Background:
- Gentamicin (GNT), a widely used aminoglycoside antibiotic, is associated with significant nephrotoxicity, limiting its clinical application.
- Understanding the molecular mechanisms underlying GNT-induced kidney damage is crucial for developing effective protective strategies.
- Diosmin (DIOS), a flavonoid, has shown potential therapeutic benefits, but its protective effects against GNT nephrotoxicity require detailed investigation.
Purpose of the Study:
- To evaluate the renoprotective potential of Diosmin (DIOS) against Gentamicin (GNT)-induced kidney injury in a rat model.
- To elucidate the underlying molecular pathways, including microRNA (miR-21, miR-155) expression and the Nrf2/HO-1 and p38-MAPK/NF-κB signaling cascades, involved in DIOS's nephroprotective action.
Main Methods:
- Rats were divided into four groups: control, GNT only, GNT + DIOS, and DIOS only.
- Assessment of kidney function markers (serum urea, creatinine, KIM-1), oxidative stress (MDA, TAC, SOD), and inflammatory cytokines (TNF-α, IL-1β).
- Evaluation of key protein expressions (Nrf2, HO-1, p38-MAPK, NF-κB p65, caspase-3, BAX, Bcl-2), microRNA levels (miR-21, miR-155), and histological kidney damage.
Main Results:
- GNT administration significantly increased kidney weight, serum markers of renal damage, oxidative stress, and inflammation, while decreasing antioxidant enzyme levels.
- GNT induced apoptosis (elevated caspase-3, BAX; reduced Bcl-2), altered miR-21 (down-regulation) and miR-155 (up-regulation) expression, and activated p38-MAPK/NF-κB pathways.
- DIOS treatment markedly reversed GNT-induced nephrotoxicity, restoring normal kidney histology, biochemical parameters, and modulating the investigated molecular pathways.
Conclusions:
- Diosmin (DIOS) exhibits significant renoprotective effects against Gentamicin (GNT)-induced nephrotoxicity in rats.
- The protective mechanisms of DIOS involve the regulation of oxidative stress, inflammation, apoptosis, and modulation of miR-21, miR-155, Nrf2/HO-1, and p38-MAPK/NF-κB signaling pathways.
- DIOS represents a promising therapeutic agent for preventing or treating GNT-induced kidney damage.
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