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<p>To investigate the prophylactic (co-treatment) effects of vitamin D (VD), thymoquinone (TQ), and their combination against gentamicin (GM)-induced acute kidney injury (AKI). Forty male Wistar rats were divided into five groups: negative control, GM-treated positive control (PC; 100 mg/kg/day), and three groups receiving GM simultaneously with VD (210 IU/kg/day), TQ (12.5 mg/kg/day), or both. The GM-treated rats developed classical AKI symptoms, including elevated serum creatinine and urea, altered urine parameters, abnormal renal histology, and increased renal cell apoptosis. Moreover, renal tissues from PC rats showed a marked increase of oxidative stress markers (MDA/H<sub>2</sub>O<sub>2</sub>/protein carbonyls) and pro-inflammatory cytokines (TNF-α/IL-1β/IL-6/IL-18/TLR2), with inhibition of antioxidants (GSH/GPx1/SOD/CAT) and interleukin-10. The expression of pathogenic mediators (NFκB-p50/iNOS/TGF-β1) was significantly upregulated, while renoprotective molecules (Nrf2/AMPK-α/AKT1/survivin) were inhibited. Both VD and TQ provided partial renal protection, with TQ showing relatively greater efficacy under the tested conditions. However, their co-administration demonstrated superior efficacy relative to both monotherapies, reflected by better restoration of renal function and histology alongside stronger reductions in oxidative stress and inflammation. This combination also resulted in a more effective downregulation of pathogenic molecules alongside enhanced expression of the renoprotective pathways. This is the first study to report a relative advantage of TQ over VD under the tested conditions and demonstrate that VD and TQ co-therapy exerted enhanced renoprotection in GM-induced AKI. These ameliorations were potentially mediated through enhanced modulation of renal oxidative stress and inflammation. However, further studies should explore VD and TQ co-therapy effects on additional pathogenic mechanisms underlying aminoglycoside-induced nephropathy.</p> Graphical Abstract <p>Illustration of the proposed protective mechanisms of vitamin D (VD), thymoquinone (TQ), and their combination against gentamicin (GM)-induced nephrotoxicity in Wistar rats. GM administration results in renal oxidative stress, inflammation, apoptosis, and structural damage, marked by elevated H<sub>2</sub>O<sub>2</sub>, malondialdehyde (MDA), and protein carbonyl content, along with increased expression of TNF-α, IL-1β, IL-6, IL-18, TLR2, iNOS, TGF-β1, and NF-κB p50. These changes are accompanied by suppression of key antioxidants (GSH, GPx1, SOD, CAT), the anti-inflammatory cytokine IL-10, the Nrf2/AMPKα/AKT1 signaling axis, and survivin. Both VD and TQ monotherapies partially attenuated these alterations by reducing oxidative stress, downregulating pro-inflammatory mediators, and restoring antioxidant defenses, thereby preserving renal architecture and function. Notably, TQ exhibited stronger protective effects than VD, while their co-administration yielded the most robust renoprotection. Red arrows represent GM-induced pathological events; blue lines represent the inhibitory effects of VD and TQ.</p> <p></p>

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Renoprotective effects of vitamin D and thymoquinone, alone and in combination, in a rat co-treatment model of gentamicin-induced acute kidney injury

  • 期刊论文

  • 发表日期：

    2026年5月21日

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  • Bassem Refaat,
  • Ahmed M. El-Sebaey,
  • Anmar Khan,
  • Talat A. Albukhari,
  • Bodour Rajab,
  • Salwa Alqurashi,
  • Waheed Filimban,
  • Hatem Sembawa,
  • Aya Megahed,
  • Ghadir Sindi,
  • Mohamed E. El-Boshy

摘要

To investigate the prophylactic (co-treatment) effects of vitamin D (VD), thymoquinone (TQ), and their combination against gentamicin (GM)-induced acute kidney injury (AKI). Forty male Wistar rats were divided into five groups: negative control, GM-treated positive control (PC; 100 mg/kg/day), and three groups receiving GM simultaneously with VD (210 IU/kg/day), TQ (12.5 mg/kg/day), or both. The GM-treated rats developed classical AKI symptoms, including elevated serum creatinine and urea, altered urine parameters, abnormal renal histology, and increased renal cell apoptosis. Moreover, renal tissues from PC rats showed a marked increase of oxidative stress markers (MDA/H2O2/protein carbonyls) and pro-inflammatory cytokines (TNF-α/IL-1β/IL-6/IL-18/TLR2), with inhibition of antioxidants (GSH/GPx1/SOD/CAT) and interleukin-10. The expression of pathogenic mediators (NFκB-p50/iNOS/TGF-β1) was significantly upregulated, while renoprotective molecules (Nrf2/AMPK-α/AKT1/survivin) were inhibited. Both VD and TQ provided partial renal protection, with TQ showing relatively greater efficacy under the tested conditions. However, their co-administration demonstrated superior efficacy relative to both monotherapies, reflected by better restoration of renal function and histology alongside stronger reductions in oxidative stress and inflammation. This combination also resulted in a more effective downregulation of pathogenic molecules alongside enhanced expression of the renoprotective pathways. This is the first study to report a relative advantage of TQ over VD under the tested conditions and demonstrate that VD and TQ co-therapy exerted enhanced renoprotection in GM-induced AKI. These ameliorations were potentially mediated through enhanced modulation of renal oxidative stress and inflammation. However, further studies should explore VD and TQ co-therapy effects on additional pathogenic mechanisms underlying aminoglycoside-induced nephropathy.

Graphical Abstract

Illustration of the proposed protective mechanisms of vitamin D (VD), thymoquinone (TQ), and their combination against gentamicin (GM)-induced nephrotoxicity in Wistar rats. GM administration results in renal oxidative stress, inflammation, apoptosis, and structural damage, marked by elevated H2O2, malondialdehyde (MDA), and protein carbonyl content, along with increased expression of TNF-α, IL-1β, IL-6, IL-18, TLR2, iNOS, TGF-β1, and NF-κB p50. These changes are accompanied by suppression of key antioxidants (GSH, GPx1, SOD, CAT), the anti-inflammatory cytokine IL-10, the Nrf2/AMPKα/AKT1 signaling axis, and survivin. Both VD and TQ monotherapies partially attenuated these alterations by reducing oxidative stress, downregulating pro-inflammatory mediators, and restoring antioxidant defenses, thereby preserving renal architecture and function. Notably, TQ exhibited stronger protective effects than VD, while their co-administration yielded the most robust renoprotection. Red arrows represent GM-induced pathological events; blue lines represent the inhibitory effects of VD and TQ.