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Published on: August 23, 2024

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

Alulu Alradhi1, Abdulrahman A Alelowi2, Ahmad H Alhowail2

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, 51452, Buraidah, Saudi Arabia. 451214231@qu.edu.sa.

Naunyn-Schmiedeberg'S Archives of Pharmacology
|July 2, 2026
PubMed

Insights

Methotrexate (MTX) causes kidney damage by increasing CXCL16 and ADAM10. Simvastatin (SIM) protects the kidneys from MTX toxicity by reducing these inflammatory markers.

Area of Science:

  • Nephrology
  • Immunology
  • Pharmacology

Background:

  • Methotrexate (MTX) is a vital chemotherapy and immunosuppressant.
  • Renal toxicity is a significant clinical limitation of MTX therapy.
  • The CXCL16/ADAM10 pathway may mediate inflammatory renal injury.

Purpose of the Study:

  • To investigate the role of CXCL16/ADAM10 in MTX-induced nephrotoxicity.
  • To evaluate the renoprotective effects of simvastatin (SIM) against MTX-induced kidney damage.

Main Methods:

  • Male Wistar rats were divided into five groups: control, SIM, MTX, and MTX + SIM (two doses).
  • MTX was administered as a single dose; SIM was given orally for 10 days.
  • Renal function, histopathology, and expression of CXCL16, ADAM10, CD3, and fibrinogen were assessed.

Main Results:

  • MTX significantly increased renal function markers and caused histopathological damage (glomerular atrophy, inflammation).
  • MTX markedly upregulated CXCL16, ADAM10, CD3, and fibrinogen expression in renal tissues.
  • SIM treatment dose-dependently improved renal function, attenuated damage, and reduced inflammatory markers.

Conclusions:

  • CXCL16 and ADAM10 are implicated in MTX-induced nephrotoxicity.
  • Simvastatin exhibits a dose-dependent renoprotective effect against MTX-induced kidney injury.
  • SIM likely modulates inflammatory pathways involving CXCL16/ADAM10 signaling for its protective effect.
Keywords:
ADAM10CXCL16MethotrexateRenal toxicitySimvastatin

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