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

doi:10.1016/j.freeradbiomed.2023.08.013

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Title:	Dapagliflozin protects against doxorubicin-induced nephrotoxicity associated with nitric oxide pathway-A translational study
Authors:	Chang, Wei-Ting Wu, Chia-Chun Liao, I-Chuang Lin, Yu-Wen Chen, Yi-Chen Ho, Chung-Han Lee, Wei-Chieh Lin, You-Cheng Chen, Zhih-Cherng Shih, Jhih-Yuan Wu, Nan-Chun Kan, Wei-Chih
Contributors:	Natl Sun Yat sen Univ, Sch Med Natl Sun Yat sen Univ, Coll Med, Doctoral Program Clin & Expt Med Natl Sun Yat sen Univ, Ctr Excellence Metab Associated Fatty Liver Dis Chi Mei Med Ctr, Dept Internal Med, Div Cardiol Southern Taiwan Univ Sci & Technol, Dept Biotechnol Chi Mei Med Ctr, Dept Internal Med, Div Nephrol Chi Mei Med Ctr, Dept Pathol Chi Mei Med Ctr, Dept Hosp & Hlth Care Adm Chia Nan Univ Pharm & Sci, Dept Pharm Chi Mei Med Ctr, Dept Surg, Div Plast & Reconstruct Surg Chi Mei Med Ctr, Dept Surg, Div Cardiovasc Surg Chia Nan Univ Pharm & Sci, Dept Hosp & Hlth Care Adm Chung Hwa Univ Med Technol, Dept Med Lab Sci & Biotechnol
Keywords:	Doxorubicin-induced nephrotoxicity Apoptosis ROS
Date:	2023
Issue Date:	2024-12-25 11:05:04 (UTC+8)
Publisher:	ELSEVIER SCIENCE INC
Abstract:	Doxorubicin (Dox) is a potent anticancer agent, but its associated organ toxicity, including nephrotoxicity, restricts clinical applications. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, has been shown to slow the progression of kidney disease in patients with and without diabetes. However, the effect of DAPA to counteract Dox-induced nephrotoxicity remains uncertain. Therefore, in this study, we aimed to elucidate the effects of DAPA in mitigating Dox-induced nephrotoxicity. We analyzed the Taiwan National Health Insurance Database to evaluate the incidence of renal failure among breast cancer patients receiving Dox treatment compared to those without. After adjusting for age and comorbidities, we found that the risk of renal failure was significantly higher in Dox-treated patients (incidence rate ratio, 2.45; confidence interval, 1.41-4.26; p = 0.0014). In a parallel study, we orally administered DAPA to Sprague-Dawley rats for 6 weeks, followed by Dox for 4 weeks. DAPA ameliorated Dox-induced glomerular atrophy, renal fibrosis, and dysfunction. Furthermore, DAPA effectively suppressed Dox-induced apoptosis and reactive oxygen species production. On a cellular level, DAPA in HK-2 cells mitigated Dox-mediated suppression of the endothelial NOS pathway and reduced Doxinduced activities of reactive oxygen species and apoptosis-associated proteins. DAPA improved Dox-induced apoptosis and renal dysfunction, suggesting its potential utility in preventing nephrotoxicity in patients with cancer undergoing Dox treatment.
Relation:	Free Radical Biology and Medicine, v.208, pp.103-111
Appears in Collections:	[Offices] 456

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