Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf-2-dependent genes by ischaemic pre-conditioning and post-conditioning: New adaptive endogenous protective responses against renal ischaemia/reperfusion injury

摘要

Aim: To investigate the impact of ischaemic pre-conditioning (Ipre) and post-conditioning (Ipost) on expression of nuclear factor erythroid 2-related factor 2 (Nrf2) gene and its dependent genes, haem oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1); inflammatory cytokines TNF-α, IL1β and ICAM-1; and apoptotic markers such as caspase-3 in renal ischaemia/reperfusion (I/R) injury. Methods: One hundred and fifty male Sprague Dawley rats were classified into five groups (each consisted of 30 rats): sham, control (I/R), Ipre + I/R, Ipre without I/R and Ipost + I/R. Serum creatinine and blood urea nitrogen (BUN) were measured at 2, 24 and 48 h after ischaemia. In kidney tissues, mRNA of Nrf2, HO-1, NQO-1, TNF-α, IL-1β and ICAM-1 and immunohistochemical expression of Nrf2 and caspase-3 were assessed. Results: Serum creatinine and BUN improved significantly in Pre + I/R group; however, they did not show any significant improvement in Post + I/R group. Also, Ipre-I/R group showed non-significant change in serum creatinine and BUN. The expression of Nrf2, HO-1 and NQO-1 is increased significantly in Pre + I/R and Pre - I/R groups, while the enhancement in Post + I/R group was non-significant. Moreover, the expression of proinflammatory cytokines (TNF-α, IL-1 and ICAM-1) and apoptotic (caspase-3) markers showed high significant attenuation in Pre + I/R group, but slight significant attenuation in Pre + I/R group. Conclusion: The renoprotective action of Ipre might include early activation and enhanced expression of Nrf2 gene and its dependent antioxidant genes, HO-1 and NOQ1, as endogenous adaptive renoprotective genes, as well as reduction in TNF-α, IL-1β, ICAM-1 and caspase-3.