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Introduction: Administration of contrast media may cause contrast-induced nephropathy (CIN), which is a severe complication during angiographic studies; it is the third most common cause of iatrogenic acute kidney injury, accounting for approximately 12% of all cases and can lead to chronic kidney disease. CIN is a sudden elevation of serum creatinine of more than 25% or ≥0.5 mg/dl in the first 48 hours. The pathological mechanisms include tubular toxicity, intrarenal vasoconstriction, and increased oxidative stress. Osthole is a nutraceutical widely used in traditional Chinese medicine and has been shown to have beneficial effects on the kidney in different experimental models. As mitochondria are targets of contrast media-induced toxicity, this research aims to study the effect of osthole as an antioxidant and its probable mitochondrial effects in contrast-induced acute kidney injury.
Methods: We studied male Wistar rats (250-300 g BW). Baseline urine and plasma samples were taken. The model of AKI was induced by dosing a combination of indomethacin (10 mg/kg), N-ω nitro-L-Arginine methyl-ester (L-NAME, 10mg/kg) and Ioversol (3g/kg) in 0.9% saline solution as vehicle intravenously in the tail vein. Rats were previously water-restricted 18 hours before the dosing. After a 48-hour follow-up, urine and plasma samples were taken to determine the induction of CIN. Osthole was administered in food (40 mg/kg) for 3 days before contrast medium injection. The groups studied were 1: Control (C), 2: Vehicle (VEH), 3: AKI and 4: AKI+Osthole (CM+OT). At the end of follow-up, animals were euthanized accord to the use an care of laboratory animals guidelines of our Institution. Tissues were frozen in liquid nitrogen and urine and plasma samples at -80°C.
Results: Contrast Media produced a significant increase in serum creatinine, blood urea nitrogen, a significant fall in creatinine clearance, increased tubular damage (NAG activity), and increased oxidative stress (lipid peroxidation and protein oxidation) with a concomitant decrease in antioxidant capacity and lower activation of the transcription factor Nrf2/ARE (Table 1). At the mitochondrial level, AKI significantly reduced complexes I, II and IV activities and markedly decreased ATP concentration. Adittionally, by WB we observed that ATP5A and biogenesis proteins (NRF1 and PGC1a) reduced expression. Previous administration of Osthole improved all the systemic, mitochondrial and renal parameters.
Conclusion: These results suggest that the previous administration of osthole has improved oxidative stress by mitochondrian complexes activity restauration, wich preserved OXPHOS and thus ATP concentrations in the renal cortex, and maintained renal function in a model of CIN. The protective effects of osthole included preserving the antioxidant system, partly mediated by the transactivation of transcriptional factor Nrf2, which could induces mitochondrial complexes restauration by biogenesis induction.