ECB-ART-55087
Toxicol Appl Pharmacol
2026 Jun 06;514:117905. doi: 10.1016/j.taap.2026.117905.
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Closantel mitigates acute kidney injury by preserving ATP-dependent sodium transport and renal hemodynamics via antioxidant mechanisms.
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Renal ischemia-reperfusion (IR) injury increases the production of reactive oxygen species (ROS), alters tubular sodium transport, and activates tubuloglomerular feedback (TGF). Closantel is an allosteric inhibitor of the SPAK/OSR1 signaling pathway. This study investigated whether closantel mitigates IR-induced acute kidney injury (AKI) by modulating the SPAK/NKCC2 pathway, renal redox balance and hemodynamics. Male Wistar rats underwent 30 min of bilateral renal ischemia and 72 h of reperfusion. Closantel (2.5, 5, or 10 mg/kg) was administered 24 h before and after ischemia. Renal IR resulted in increased serum creatinine (∼70%), albuminuria (∼400%), tubulointerstitial injury score (8-fold), and fractional excretion of Na+, K+, and Cl- (by 200-450%). Cortical (Na++K+) ATPase activity decreased by 40%, while medullary activity increased by 133%. Oxidative stress markers (ROS, lipid peroxidation, NADPH oxidase) were elevated, and antioxidant defenses (SOD, catalase) were impaired. Closantel (10 mg/kg) significantly inhibited the SPAK/NKCC2 pathway, reducing protein levels of SPAK, total NKCC2, and phosphorylated NKCC2 (p-NKCC2) by ∼70%. This was accompanied by normalized fractional excretion of Na+, K+, and Cl-, reflecting restored tubular reabsorptive efficiency. In the cortex, closantel induced a supraphysiological upregulation of (Na++K+)ATPase activity, whereas medullary activity was restored to Sham levels. Furthermore, closantel improved glomerular filtration rate and renal blood flow while reducing renal vascular resistance. In conclusion, closantel protects against AKI by inhibiting the SPAK/p-NKCC2 signaling axis, mitigating oxidative stress, and restoring renal reabsorptive efficiency and hemodynamics.
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