Abstract 284: Lower Nrf2 Activity And Decreased Levels Of Pdi And No In The Kidney Contributes To Hypertension In The Aging Fbns

Abstract

We recently reported that age-associated oxidative stress is causal to higher renal angiotensin AT1 receptor (AT1R) function and blood pressure (BP) in the aging Fischer Brown Norway (FBN) rats. This suggests that redox homeostasis is critical for normal AT1R function and blood pressure (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. Kidneys from adult (3-month) and aged (21-month) FBN rats were isolated. Nrf2 transcription factor, involved in transcriptional activity of diverse antioxidant enzymes genes, was determined in the nuclear and cytosolic fractions of cortical tissues by Western blotting. Nuclear accumulation of Nrf2 is an index of its activation. Protein disulfide isomerase (PDI), an enzyme involved in isomerization reaction, was determined in the cortical homogenates. Moreover, nitrate/nitrite levels were determined in the urine as an index of NO levels in the kidney. We found that the levels of Nrf2 were decreased (adult vs old: 1.86±0.69 vs 0.87±0.18, -53.2%) in the nuclei but increased (adult vs old: 1.20±0.27 vs 1.51±0.36, +25.8%) in the cytosol of aging kidneys. PDI levels also were decreased (adult vs old: 5.38±2.60 vs 3.59±1.76, -33.3%) in the aging kidneys. Furthermore, nitrate/nitrite levels were lower (adult vs old: 372±73 vs 211±30, -43.3%) in the urine from aged than in adult rats. These data suggest that impaired Nrf2 activity in the aging kidneys contributes to increased oxidative stress, renal AT1R function and BP in the aged FNBs. Furthermore, these data also indicate that PDI in an NO-dependent pathway regulates Nrf2 activity contributing to redox-balance in the kidney.