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<p>Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent; however, one of clinical limitations of its use is renal toxicity. CXCL16 is a transmembrane chemokine that can be cleaved by ADAM family proteases, particularly ADAM10, to generate a soluble form that acts as a chemoattractant for CXCR6-expressing cells such as T lymphocytes. This process may contribute to inflammatory renal injury. This study investigated the role of CXCL16/ADAM10 in MTX-induced nephrotoxicity and assessed the renoprotective effects of simvastatin (SIM). Fifty male Wistar rats were randomly assigned to five groups: control, SIM (40&#xa0;mg/kg), MTX (20&#xa0;mg/kg) and two combination groups receiving MTX with SIM (10 or 40&#xa0;mg /kg). SIM was administered orally for 10&#xa0;days, while MTX was administered as a single i.p. dose on day 4. Hematological parameters, markers of renal function, and renal histopathology were assessed. In addition, the expression of CXCL16, ADAM10, CD3, and fibrinogen was evaluated. MTX administration significantly elevated renal function markers compared with the control and SIM groups. Histopathological analysis revealed glomerular atrophy and mononuclear inflammatory cell infiltration in MTX-treated rats. Moreover, MTX markedly increased the expression of CXCL16, ADAM10, CD3, and fibrinogen in the glomeruli and tubulointerstitial regions. Treatment with SIM significantly improved renal function markers, attenuated histopathological damage, and reduced the expression of these inflammatory and injury-related proteins. CXCL16 and its processing enzyme ADAM10 play important roles in MTX-induced renal toxicity. SIM demonstrated a dose-dependent protective effect against MTX-induced renal injury, likely through modulation of inflammatory pathways involving CXCL16/ADAM10 signaling.</p>

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Role of CXCL16/ADAM10 signaling in methotrexate-induced nephrotoxicity and its modulation by simvastatin

  • 期刊论文

  • 发表日期：

    2026年7月2日

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  • Alulu Alradhi,
  • Abdulrahman A. Alelowi,
  • Ahmad H. Alhowail,
  • Maha A. Aldubayan,
  • Mohamed S. Abdel-Bakky

摘要

Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent; however, one of clinical limitations of its use is renal toxicity. CXCL16 is a transmembrane chemokine that can be cleaved by ADAM family proteases, particularly ADAM10, to generate a soluble form that acts as a chemoattractant for CXCR6-expressing cells such as T lymphocytes. This process may contribute to inflammatory renal injury. This study investigated the role of CXCL16/ADAM10 in MTX-induced nephrotoxicity and assessed the renoprotective effects of simvastatin (SIM). Fifty male Wistar rats were randomly assigned to five groups: control, SIM (40 mg/kg), MTX (20 mg/kg) and two combination groups receiving MTX with SIM (10 or 40 mg /kg). SIM was administered orally for 10 days, while MTX was administered as a single i.p. dose on day 4. Hematological parameters, markers of renal function, and renal histopathology were assessed. In addition, the expression of CXCL16, ADAM10, CD3, and fibrinogen was evaluated. MTX administration significantly elevated renal function markers compared with the control and SIM groups. Histopathological analysis revealed glomerular atrophy and mononuclear inflammatory cell infiltration in MTX-treated rats. Moreover, MTX markedly increased the expression of CXCL16, ADAM10, CD3, and fibrinogen in the glomeruli and tubulointerstitial regions. Treatment with SIM significantly improved renal function markers, attenuated histopathological damage, and reduced the expression of these inflammatory and injury-related proteins. CXCL16 and its processing enzyme ADAM10 play important roles in MTX-induced renal toxicity. SIM demonstrated a dose-dependent protective effect against MTX-induced renal injury, likely through modulation of inflammatory pathways involving CXCL16/ADAM10 signaling.