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Dapagliflozin protects against doxorubicin-induced nephrotoxicity associated with nitric oxide pathway-A

Wei-Ting Chang1, Chia-Chun Wu2, I-Chuang Liao3

  • 1School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.

Free Radical Biology & Medicine
|August 7, 2023
PubMed

Insights

Dapagliflozin (DAPA) may protect against Doxorubicin (Dox)-induced kidney damage. This study found DAPA reduced renal failure risk and improved kidney function in Dox-treated rats and cells, suggesting DAPA could prevent Dox nephrotoxicity.

Area of Science:

  • Oncology
  • Nephrology
  • Pharmacology

Background:

  • Doxorubicin (Dox) is a vital chemotherapy drug but causes significant kidney toxicity (nephrotoxicity), limiting its use.
  • Dapagliflozin (DAPA), a SGLT2 inhibitor, is known for kidney protective effects in diabetic and non-diabetic kidney disease.
  • The potential of DAPA to mitigate Dox-induced nephrotoxicity is not well understood.

Purpose of the Study:

  • To investigate the protective effects of Dapagliflozin (DAPA) against Doxorubicin (Dox)-induced nephrotoxicity.
  • To evaluate the association between Dox treatment and renal failure risk in breast cancer patients.
  • To explore the mechanisms underlying DAPA's renoprotective effects against Dox in preclinical models.

Main Methods:

  • Retrospective analysis of the Taiwan National Health Insurance Database to assess renal failure incidence in Dox-treated versus non-Dox-treated breast cancer patients.
  • Oral administration of DAPA to Sprague-Dawley rats for 6 weeks, followed by Dox treatment for 4 weeks.
  • In vitro studies using HK-2 cells to examine DAPA's effects on Dox-induced cellular damage, apoptosis, and oxidative stress.

Main Results:

  • Doxorubicin treatment was associated with a significantly higher risk of renal failure in breast cancer patients (IRR=2.45, p=0.0014) after adjusting for confounders.
  • DAPA administration ameliorated Dox-induced glomerular atrophy, renal fibrosis, and kidney dysfunction in rats.
  • DAPA suppressed Dox-induced apoptosis and reactive oxygen species (ROS) production, and improved endothelial NOS (eNOS) pathway function in HK-2 cells.

Conclusions:

  • Dapagliflozin demonstrates significant renoprotective effects against Doxorubicin-induced nephrotoxicity in both clinical and preclinical settings.
  • DAPA mitigates Dox-induced kidney damage by reducing apoptosis, oxidative stress, and improving cellular signaling pathways.
  • Dapagliflozin shows promise as a therapeutic agent to prevent or reduce kidney toxicity in cancer patients receiving Doxorubicin chemotherapy.
Keywords:
ApoptosisDoxorubicin-induced nephrotoxicityROS

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