Nrf2 Activation Improves Mitochondrial Function in Kidneys of Aged F344 Rats

Abstract

Age is a major contributing factor for the development of many chronic pathologies including renal-cardiovascular and neurological disorders. People aged 65 years or above are at a high risk of developing kidney dysfunction. Aging is frequently associated with increased oxidative stress and impaired mitochondrial function. Studies have shown that the expression and function of Nrf2, a critical redox-sensitive transcription factor, is adversely affected during aging. However, the role of Nrf2 in the regulation of mitochondrial function in the aged kidney is not clear. Previous studies in our lab with Fischer 344(F344) rats have shown that mitochondrial respiration is impaired in the kidneys of aged rats along with decreased kidney function. The present study aimed to investigate the role of Nrf2 in the improvement of mitochondrial function in aged rat kidneys. Adult and aged Fischer 344 rats were kept on drinking water (control) or treated with sulforaphane, a potent activator of Nrf2, in drinking water. Treatment with sulforaphane significantly increased the Nrf2 expression in kidneys of aged rats compared to control aged rats. The level of Keap1, a repressor of Nrf2, was markedly increased in kidneys of aged rats which was significantly decreased by sulforaphane treatment. The treatment of adult rats with sulforaphane didn't show any increase in kidney Nrf2 expression compared with age-matched control rats. Nrf2 activation also significantly decreased the elevated levels of oxidative stress and increased the total antioxidant capacity in urine of aged rats compared to aged control. Glomerular damage indicators, proteinuria, and albuminuria, which were significantly high in aged rats were reduced by sulforaphane treatment. We found that antioxidant heme oxygenase 1(HO1) and mitochondrial transcription factor A (TFAM) were significantly reduced in the kidneys of aged rats. Nrf2 activation with sulforaphane improved the protein levels of both HO1 and TFAM. The impaired mitochondrial respiration was significantly improved by Nrf2 activation in renal cortical mitochondria of aged rats when compared to aged controls. Our study provides novel insights as it relates to the regulation of renal mitochondrial function by Nrf2 in aged rats and identifies cortical mitochondria-Nrf2 interaction as a therapeutic target to mitigate renal dysfunction in the aging population.