Dapagliflozin Exerts Renoprotective Effect by Activating the Nrf2/HO-1 Pathway in Glycerol-Induced Acute Kidney Injury

Background: One serious clinical consequence of rhabdomyolysis is acute kidney injury (AKI). Dapagliflozin (Dapa) is a novel anti-diabetic drug for type 2 diabetes. Beyond its glucose-lowering action, evidence from both human and animal studies highlights its additional anti-inflammatory and antioxidative benefits. Objective: This study aimed to demonstrate for the first time the effect of protection of Dapa via triggering the Nrf2/HO-1 pathway to counteract glycerol-induced AKI. Materials and methods: Four groups of forty male Wistar rats were established (n = 10 each): (1) Normal control group (normal saline), (2) glycerol group (10 ml/kg, intramuscular), (3) glycerol + Dapa group (1 mg/kg, p.o.) and (4) Dapa (1 mg/kg, p.o.). After 7 days, Evaluations of renal function were conducted through the measurement of blood urea nitrogen (BUN) and serum creatinine levels (sCr). Oxidative stress markers, including malondialdehyde (MDA) and superoxide dismutase (SOD), were determined. Kidney injury molecule-1 (Kim-1), histopathological alterations, and inflammatory markers such as nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) were also evaluated. In addition, antioxidant defense mechanisms were investigated by assessing nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in kidneys. Results: Pretreatment with Dapa improved kidney function by lowering sCr, BUN, and Kim-1 and reducing histopathological damage. It also suppressed glycerol-induced inflammation of TNF-α and NF-κB, while enhancing antioxidant defenses through Nrf2/HO-1 pathway activation. Conclusion: Dapa pretreatment improved kidney function in a rat model of glycerol-induced rhabdomyolysis-associated renal damage by inhibiting the inflammatory response and lowering oxidative stress.