Protective effects and mechanisms of dapagliflozin on renal ischemia/reperfusion injury

• Published in: Transplant immunology Vol. 84; p. 102010
• Main Authors: Qiuxiao-Zhu, Huiyao-Hao, Li, Na, Zibo-Liu, Qian-Wang, Linyi-Shu, Lihui-Zhang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2024
• Subjects: BMP4; Dapagliflozin; I/R; Kidney; PI3K-AKT signaling pathway; BMP4; PI3K-AKT signaling pathway; Dapagliflozin; I/R; Kidney
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2024.102010

Renal diseases have a significant negative impact on human health and the quality of life. Renal ischemia/reperfusion (I/R) injury is considered as one of the leading causes of renal dysfunction and tissue damage. Oxidative stress and inflammation are responsible for cellular apoptosis playing critical roles in renal I/R injury. Recent studies suggested that dapagliflozin—a medication used to treat Type 2 Diabetes—may exert protective effects on I/R injury in kidneys by alleviating oxidative stress and inflammation. Our study evaluated the protective effects of dapagliflozinon in renal I/R injury. A group of 32 male Sprague-Dawley rats were divided into four groups: 1) control group without any manipulation; 2) sham-operated control group with surgery but without I/R injury; 3) experimental group with 30-min I/R injury; and 4) therapeutic group with 30-min IR injury and dapagliflozin therapy. The fourth therapeutic group received 1 mg/kg dapagliflozin delivered once daily by oral gavage. All rats were evaluated by measurements of neutrophil gelatinase-associated lipocalin (NGAL), creatinine kinase (CR), blood urea nitrogen (BUN), kidney injury molecule-1 (KIM-1), myoglobin (MYO), creatinine kinase (CK), lactate dehydrogenase (LDH) LD, GSH, superoxide dismutase (SOD), MDA, interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a and glutathione peroxidase (GSH-Px) levels. TUNEL and flow cytometry assays evaluated apoptosis. Overall, the 30-min exposure to I/R injury significantly elevated levels of NGAL, CR, BUN, CK, LDH, KIM-1, and MYO (all p < 0.05). Inflammatory cytokine levels (IL-6 and TNF-a) were also increased after I/R injury (p > 0.05). At the same time, I/R injury decreased levels of SOD and GSH-Px (p > 0.05). In contrast, administration of dapagliflozin following I/R injury reduced renal damage, enhanced antioxidant capacity, and suppressed inflammatory responses (all p > 0.05), thus improving renal function, while reducing oxidative stress status and inflammatory responses. Further investigations revealed that dapagliflozin exerted its protective effects on renal tissues by activating the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway, inhibiting cellular apoptosis, and promoting proliferation and autophagy through bone morphogenetic protein 4 (BMP4). These findings documented that dapagliflozin protected kidneys from I/R injury suggesting its therapeutic potential. •Dapagliflozin administration following renal ischemia/reperfusion (I/R) injury in mice reduces renal damage.•Dapagliflozin enhances antioxidant capacity and suppresses inflammatory responses in renal tissues.•Dapagliflozin exerts its protective effects through the activation of the PI3K-AKT signaling pathway, inhibition of cellular apoptosis, and promotion of proliferation and autophagy mediated by BMP4.