Activation of Nrf2 Restores Klotho Expression and Attenuates Oxidative Stress and Inflammation in CKD

Abstract

Background: Chronic kidney disease (CKD) causes klotho deficiency, oxidative stress and inflammation which are common features and major mediators of progression of renal disease. Oxidative stress in CKD is, partly, due to impaired activation of Nrf2, the master regulator of genes encoding antioxidant and cytoprotective molecules. Oxidative stress inhibits klotho expression in the kidney. Given the role of Nrf2 dysfunction in the pathogenesis of oxidative stress in CKD, we hypothesized that treatment with Nrf2 activator, dh404, may restore renal klotho expression and attenuate oxidative stress and inflammation in CKD. Methods: Male SD rats were subjected to 5/6 nephrectomy (CKD) or sham operation. The CKD rats were randomized to receive dh404 (2mg/kg/day) or vehicle for 12 weeks. At the conclusion of the observation period tail arterial pressure was measured and 24-hr urine was collected. Animals were then euthanized and blood and kidneys were harvested. Results: Compared to the control group, untreated CKD rats exhibited marked reduction of klotho abundance in the remnant kidney. This was associated with interstitial inflammation, local and systemic oxidative stress, NFkB activation, impaired Nrf2 activity and reduced expression of the key Nrf2 target gene products. Administration of dh404 reversed klotho deficiency, restored Nrf2 activity and expression of its key target gene products and attenuated oxidative stress and inflammation and NFkB activity in the renal tissue. Conclusion: Restoration of Nrf2 activity reversed klotho deficiency and attenuated oxidative stress and inflammation in remnant kidneys of CKD rats.