Involvement of antioxidant defense mechanisms in the pathogenesis of renal damage

用Nrf2基因敲除小鼠和Keap1基因敲除小鼠研究了环孢素A诱导的肾毒性。众所周知，Keap1-Nrf2系统在促进抗氧化机制方面发挥着核心作用。在Nrf2基因敲除小鼠中，抗氧化剂Keap1-Nrf2系统失活，环孢素A诱导肾脏氧化应激和肾小管损伤，提示Keap1-Nrf2系统在环孢素肾毒性的发病机制中起保护作用。然而，在Keap1基因敲除的小鼠中，抗氧化机制被结构性激活，肾脏损伤并未减轻。这些结果表明，虽然抗氧化剂系统参与了减轻环孢素肾毒性，但不受控制地激活Keap1-Nrf2系统并不总是伴随着减轻环孢素肾毒性的有利作用，提示在环孢素肾毒性的发病机制中可能存在除氧化应激之外的其他机制。

Cyclosporine-induced nephrotoxicity was studied in Nrf2 knockout mice and Keap1 knockdown mice. The Keap1-Nrf2 system is known to play a central role in promoting antioxidant mechanisms. In Nrf2 knockout mice, in which the antioxidant Keap1-Nrf2 system is inactivated, cyclosporine A induces oxidative stress in the kidney and tubular damage, suggesting that Keap1-Nrf2 system plays a protective role in the pathogenesis of cyclosporine nephrotoxicity. However, in Keap1 knockdown mice, in which antioxidant mechanisms are constitutively activated, renal damage was not attenuated. These data suggest that, although antioxidant system is involved in attenuating cyclosporine nephrotoxicity, uncontrolled activation of Keap1-Nrf2 system is not always accompanied by beneficial effects in attenuating cyclosporine nephrotoxicity, suggesting that there may be some mechanisms other than oxidative stress in the pathogenesis of cyclosporine nephrotoxicity.