Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. The organic anion transporter 5 (Oat5) is exclusively localized in the kidney. Oat5 urinary excretion was recently proposed as a potential early biomarker of acute kidney injury (AKI). The aim of this study was to evaluate Oat5 renal expression and its urinary excretion in rats exposed to different doses of cisplatin, in comparison with traditional markers of renal injury, like renal histology, creatinine and urea plasma levels, creatinine clearance, protein and glucose urinary levels and urinary alkaline phosphatase (AP) activity. Male Wistar rats were treated with a single injection of cisplatin at different doses of 1, 2, 5 and 10 mg/kg b.w., i.p. (Cis1, Cis2, Cis5 and Cis10, n = 4, respectively) and experiments were carried out 48 h after cisplatin administration. The renal expression of Oat5 was evaluated by immunohistochemistry and Western blotting. Oat5 abundance, AP activity, creatinine, glucose and proteins were assayed in urine. Creatinine clearance and creatinine and urea plasma levels were also evaluated. In this experimental model, plasma urea and creatinine levels, creatinine clearance, AP urinary activity and protein and glucose urinary levels were significantly modified only at the highest cisplatin dose of 10 mg/kg b.w., i.p., as compared to control rats. In contrast, Oat5 urinary abundance was increased in a dose-related manner after the administration of cisplatin. Oat5 urinary abundance was elevated at a dose as low as 1 mg/kg b.w., i.p., implying renal perturbation, when no modifications of traditional markers of renal injury are yet observed. Oat5 renal expression was decreased in a dose-related manner, both in homogenates and apical membranes from cisplatin-treated kidneys. The increase in urinary Oat5 excretion might explain the decrease in the amount of Oat5 molecules in the renal tubule cells. Hence, the preclinical animal results showed in this work propose that Oat5 urinary excretion might potentially serve as a non-invasive early biomarker of cisplatin-induced AKI.

Cisplatin is a widely used citostatic drug employed in the treatment of many solid tumors. Its principal side-effect is nephrotoxicity. The organic anion transporter 5 (Oat5) is exclusively expressed in the kidneys. The aim of this study was to evaluate the time course of Oat5 urinary excretion and changes in conventional biomarkers, such as creatinine and urea plasma levels (Urp and Crp), and protein and glucose urinary levels (Pu and Gluu), between others, and compared them to the onset and progression of histological changes after cisplatin treatment. Male Wistar rats were treated with cisplatin with 5 mg/kg b.w., i.p., and experiments were carried out after 2, 4, 7 and 14 days of treatment. Two days after cisplatin administration, only Oat5 urinary excretion was found markedly modified. On day 4, Urp, Crp, PU and GluU were increased. By the seventh day, a severe impairment in tubular architecture was observed, and from this point and thereon, Oat5 urinary excretion and PU showed a tendency to return to their basal values. Meanwhile, Urp, Crp and GluU tended to return to their basal values by the day 14 of treatment, when kidney morphology showed an important recovery. So Oat5 urinary abundance was elevated 2 days after cisplatin treatment, when no modifications of traditional markers of renal injury were still observed. Therefore, the results showed in this work, in addition to previous data obtained by our group, propose that Oat5 urinary excretion might potentially serve as a noninvasive early biomarker of cisplatin-induced nephrotoxicity.

BUO was associated with down-regulation of OAT1 and OAT3 in basolateral plasma membranes from proximal tubule cells, thus these carriers may play important roles in the impaired organic anion excretion displayed in the obstructed kidney.