Renoprotective effect of roflumilast against amikacin- induced nephrotoxicity: upregulation of Nrf2 signaling, inhibition of cytokines, and renal apoptosis.
Abdel-Kareem Mona A, Taha Medhat, Ahmed Magda E, Atef Reham Mohammed, El-Kholy Sanad S, Zidane Noura H, Elmitwalli Mohammed E, Baokbah Tourki A S, El-Shenbaby Ibrahim, Ali Kareem Gomaa Al Sayed, Halloull Noha M, Megahed Omnia Hassan, Esa Rehab Abd El Azeem, Mohamed Ahmed Nahed Zaky, Hussin Emadeldeen
Abstract
ABSTARCTAmikacin (AK), a potent aminoglycoside antibiotic, is known to induce nephrotoxicity. This study evaluated the renoprotective effects of ROF, a selective PDE4 inhibitor, against AK-induced renal injury in Wistar rats. Forty male rats were divided into four groups (n = 10): Control (saline), ROF-only (1.5 mg/kg/day orally for 6 days), AK-only (single intraperitoneal injection of 1.2 g/kg on day 3), and AK+ROF (co-treatment). Renal function was assessed via serum creatinine and BUN. Oxidative stress was evaluated by measuring MDA and the antioxidants GSH, SOD, and CAT. The expression of key proteins in the Nrf2/HO-1, NF-κB, and apoptotic pathways was analyzed using ELISA and IHC. Kidney histopathology was examined using H&E, PAS, and Masson's trichrome staining. AK administration significantly elevated serum creatinine and BUN levels, increased lipid peroxidation, and suppressed antioxidant enzymes (SOD, CAT, and GSH). It also upregulated NF-κB along with TNF-α, IL-1β, and IL-6, and enhanced apoptotic markers (caspase-3, Bax) while reducing Bcl-2 expression. Histopathological analysis revealed severe tubular degeneration and inflammatory infiltration in the AK group. The most prominent finding was that ROF co-treatment robustly activated the Nrf2/HO-1 antioxidant pathway, leading to a comprehensive protective effect. ROF significantly ameliorated renal dysfunction, restored antioxidant enzyme activities, and reduced lipid peroxidation. It concurrently suppressed the NF-κB inflammatory cascade and modulated apoptotic signaling. These biochemical improvements were corroborated by marked histopathological recovery. In conclusion, ROF demonstrated potent renoprotection against AK-induced injury primarily through Nrf2/HO-1 pathway activation, which underpinned its synergistic antioxidant, anti-inflammatory, and anti-apoptotic actions, supporting its potential as a therapeutic strategy to mitigate aminoglycoside nephrotoxicity.
Key Findings
- Roflumilast (ROF) co-treatment activated the Nrf2/HO-1 antioxidant pathway in rats with amikacin-induced nephrotoxicity.
- ROF ameliorated renal dysfunction by restoring antioxidant enzyme activities (SOD, CAT, GSH) and reducing lipid peroxidation.
- ROF suppressed NF-κB-mediated inflammatory cytokines (TNF-α, IL-1β, IL-6) and modulated apoptotic markers, reducing kidney tissue damage.
Clinical Significance
ROF shows potential as a therapeutic agent to protect against aminoglycoside-induced kidney injury by enhancing antioxidant defenses and reducing inflammation and apoptosis.
Citation
Abdel-Kareem Mona A, Taha Medhat, Ahmed Magda Eet al.. Renoprotective effect of roflumilast against amikacin- induced nephrotoxicity: upregulation of Nrf2 signaling, inhibition of cytokines, and renal apoptosis. Drug and chemical toxicology. 2026-Jun-22.