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Aims <p>This study examined the renoprotective effect of Piribedil against cyclophosphamide (CP)-induced nephrotoxicity through modulation of adenosine monophosphate–activated protein kinase (AMPK)/sirtuin-1 (SIRT1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinases (MAPKs), and Toll-like receptor-4 (TLR4)/NOD-like receptor protein-3 (NLRP3) pathways, as well as renal injury markers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase–associated lipocalin (NGAL).</p> Main methods <p>Male rats were divided into four groups (n = 8). Controls received distilled water plus saline; the CP group received a single CP dose (200&#xa0;mg/kg, i.p.) on day 7; Piribedil groups received 15 or 40&#xa0;mg/kg/day for 10&#xa0;days with CP on day 7. Renal function, oxidative stress, inflammation, and injury markers (KIM-1 and NGAL) were assessed via biochemical assays, histopathology, immunohistochemistry, and quantitative real-time PCR (qRT-PCR).</p> Key findings <p>CP caused significant renal dysfunction, elevating blood urea nitrogen (BUN), serum creatinine (SCr), NGAL, and KIM-1, increasing oxidative stress (malondialdehyde [MDA], inducible nitric oxide synthase [iNOS]) and reducing nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione (GSH). CP also upregulated inflammatory mediators (interleukin-1β [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α], nuclear factor-κB p65 [NF-κB p65]) and enhanced TLR4, NLRP3, and MAPKs, while suppressing AMPK, SIRT1, and PI3K/Akt signaling. Piribedil reversed these changes, improving renal function, lowering oxidative and inflammatory markers, and normalizing BUN, SCr, KIM-1, and NGAL. Histology confirmed reduced renal damage.</p> Significance <p>Piribedil effectively protects against CP-induced nephrotoxicity by modulating AMPK/SIRT1 and related oxidative and inflammatory pathways, supporting its potential use in drug-induced kidney injury.</p>

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Modulation of AMPK/SIRT1 signaling by piribedil attenuates cyclophosphamide-induced nephrotoxicity via PI3K/Akt, MAPKs, and TLR4/NLRP3 pathways with regulation of KIM-1/NGAL

  • 期刊论文

  • 发表日期：

    2026年2月3日

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  • Ahmed M. El-Dessouki,
  • Tarek A. Yousef,
  • Mashael A. Alghamdi,
  • Arwa Omar Al Khatib,
  • Bassant M. Barakat,
  • Asmaa Ramadan,
  • Nada A. Ashour,
  • Sahar K. Ali,
  • Mohamed N. Goda,
  • Ahmed A. Al-Karmalawy

摘要

Aims

This study examined the renoprotective effect of Piribedil against cyclophosphamide (CP)-induced nephrotoxicity through modulation of adenosine monophosphate–activated protein kinase (AMPK)/sirtuin-1 (SIRT1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinases (MAPKs), and Toll-like receptor-4 (TLR4)/NOD-like receptor protein-3 (NLRP3) pathways, as well as renal injury markers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase–associated lipocalin (NGAL).

Main methods

Male rats were divided into four groups (n = 8). Controls received distilled water plus saline; the CP group received a single CP dose (200 mg/kg, i.p.) on day 7; Piribedil groups received 15 or 40 mg/kg/day for 10 days with CP on day 7. Renal function, oxidative stress, inflammation, and injury markers (KIM-1 and NGAL) were assessed via biochemical assays, histopathology, immunohistochemistry, and quantitative real-time PCR (qRT-PCR).

Key findings

CP caused significant renal dysfunction, elevating blood urea nitrogen (BUN), serum creatinine (SCr), NGAL, and KIM-1, increasing oxidative stress (malondialdehyde [MDA], inducible nitric oxide synthase [iNOS]) and reducing nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione (GSH). CP also upregulated inflammatory mediators (interleukin-1β [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α], nuclear factor-κB p65 [NF-κB p65]) and enhanced TLR4, NLRP3, and MAPKs, while suppressing AMPK, SIRT1, and PI3K/Akt signaling. Piribedil reversed these changes, improving renal function, lowering oxidative and inflammatory markers, and normalizing BUN, SCr, KIM-1, and NGAL. Histology confirmed reduced renal damage.

Significance

Piribedil effectively protects against CP-induced nephrotoxicity by modulating AMPK/SIRT1 and related oxidative and inflammatory pathways, supporting its potential use in drug-induced kidney injury.