Comparação entre o treinamento intervalado de alta intensidade e treinamentos contínuos sobre a sinalização de Klotho/NRF2 e o estado redox renal em ratas com nefrotoxicidade induzida por cisplatina.

Abstract

Cisplatin (cis-diamminedichloroplatinum II, CDDP) is a chemotherapy agent used to treat various solid tumors. However, its use is limited by nephrotoxicity, which culminates in acute kidney injury (AKI). Oxidative and nitrosative stress are the main mechanisms involved in CDDP-induced nephrotoxicity. Exercise training can promote antioxidant effects by activating signaling pathways, such as the Klotho/Nrf2 pathway. However, the effects of manipulating training variables, like intensity, on these antioxidant effects are not yet well established. Therefore, this study aims to compare the effects of low (LIT), moderate (MIT), and high- intensity interval training (HIIT) on the renal redox state through modulation of the signaling pathway Klotho/Nrf2 of rats with CDDP-induced AKI. To this end, Wistar rats were divided into five groups (n=7): sedentary control (C+S); CDDP and sedentary (CDDP+S); CDDP and submitted to LIT (CDDP+LIT); CDDP and submitted to MIT (CDDP+MIT); and CDDP and submitted to HIIT (CDDP+HIIT). The training protocols were carried out on a motorized treadmill for 8 weeks. After this period, we administered a single injection of CDDP (5 mg/kg), or saline solution, to induce AKI. Seven days after the CDDP injection, the rats were introduced into metabolic cages to collect 24-hour urine samples, and then they were euthanized to collect kidneys and trunk blood. The tubular function was analyzed through the excretion fraction (EF) of electrolytes; the tubular structure; markers of nitro-oxidative lesions to cellular macromolecules (lipids, proteins, and DNA); the levels and activity of antioxidant enzymes, and the expression of α-Klotho and Nrf2 in kidney tissue. Our data demonstrate that CDDP caused loss of the brush border and reduced reabsorptive function of renal tubules, reduced klotho expression, and increased markers of oxidative and nitrosative damage to cellular macromolecules, such as lipids (4-HNE and TBARS), proteins (carbonylated proteins and 3- NT) and DNA (8-OHDG). However, training protocols were able to reduce all these changes in an intensity-dependent manner and, therefore, with more prominent effects with HIIT. Our training protocols also enhanced renal antioxidant defenses, showing increased expression of antioxidant enzymes (SOD-1, catalase, and GPx) and increased enzymatic activity (catalase and GPx). Such effects may have been, at least in part, mediated by the activation of the Nrf2

pathway, also in an intensity-dependent manner. In conclusion, our results suggest that HIIT promoted more pronounced renoprotective effects than LIT and MIT, improving the redox state by activating the Klotho/Nrf2 signaling pathway in rats with CDDP-induced nephrotoxicity.