Role of Transcription Factor Nrf2 in the Regulation of Kidney Function During Aging



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Age is one of the major risk factors for the development of various chronic pathologies including kidney and cardiovascular disorders. Oxidative stress and mitochondrial dysfunction are implicated in age-related kidney diseases. Redox-sensitive transcription factor, nuclear factor erythroid 2–related factor 2 (Nrf2), regulates oxidative stress and mitochondrial function. It is reported that Nrf2 signaling is altered during aging, but the exact implications of altered Nrf2 signaling on mitochondrial function in the aged kidneys are not yet clear. Here we investigate the role of Nrf2 activation on the regulation of mitochondrial and kidney function during aging. Adult (2–4-month-old) and aged (20–24-month-old) male Fischer 344 rats were treated with sulforaphane (Nrf2 activator, 15mg/kg body wt./day) in drinking water for four weeks. Age-matched control rats received drinking water alone. Aged rat kidneys had significant impairment in Nrf2 signaling compared to adult control rats as evidenced by decreased expression of Nrf2 target proteins such as heme oxygenase 1 and mitochondrial transcription factor A. Additionally, Keap1 (a Nrf2 repressor) was significantly high in aged rats compared to adult control. Renal mitochondrial respiration was markedly decreased, electron transport chain complex expression and activities were significantly impaired in aged rats compared to adult control rats. Sulforaphane significantly improved Nrf2 expression, nuclear translocation and activity, increased HO1 and TFAM expression, and decreased Keap1 protein in aged rat kidneys but not in adult rats. Also, Nrf2 activation by sulforaphane significantly improved mitochondrial respiration, electron transport chain complex expression, and activities. Consequently, Nrf2 activation significantly decreased oxidative stress, glomerular sclerosis, and kidney fibrosis in aged rats compared to aged control rats. To summarize, our study shows that Nrf2 activation improved mitochondrial function, reduced oxidative stress, glomerular damage, and kidney injury in aged rats. Taken together, improved mitochondrial function by Nrf2 provides novel insights into the protective role of Nrf2 pathway in kidneys during aging. Our study identifies cortical Nrf2-mitochondria interaction as a potential therapeutic target to mitigate kidney dysfunction in the aging population.



Nrf2, Aging, Kidney disease, Mitochondria, Oxidative stress