PDI via Nrf2 Contributes to the Regulation of Renal AT1 Receptor Function and Blood Pressure

Abstract

We recently reported that age‐associated oxidative stress plays a causal role in high renal angiotensin AT1 receptor (AT1R) function and blood pressure (BP) in the aging Fischer Brown Norway (FNB) rats. This indicates that redox balance is crucial for normal AT1R function and BP. Our objective was to understand the mechanism responsible for the higher oxidative stress in the aging kidneys contributing to impaired AT1R function and high BP in the aged FBNs. Keap1‐Nrf2 system is the master cytoprotective regulatory pathway in the kidney against oxidative stress. Nrf2 transcription factor protects kidney from oxidative stress by activating the transcription of diverse antioxidant and detoxifying enzymes. Kelch‐like ECH‐associated protein 1 (keap1) constitutively represses Nrf2 activity by sequestering Nrf2 in cytosol. We hypothesize that protein disulfide isomerase (PDI), an enzyme involved in isomerization reaction, regulates keap1 and Nrf2. Nrf2, keap1 and PDI were determined by Western blotting and/or immunohistochemistry in both the kidney cortical tissue of FBNs and human kidney 2 (HK2) cells. We found that the aging kidney had low levels of PDI, which was associated with low nuclear levels of Nrf2 and high cytosolic levels of keap1 in the aging FBNs. Moreover, PDI inhibition by bacitracin in HK2 cells significantly reduced Nrf2 accumulation in the nuclei. PDI siRNA treatment in HK2 cells decreased the level of PDI while increased the level of keap1. These data suggest that PDI via keap1 and Nrf2 may be involved in redox balance, contributing to the regulation of AT1R function and BP in aging.Source of Research Support: NIH/NIA, AG039856