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Activation of Transcription Factor Nrf2 Ameliorates Age‐Associated Decline in Kidney Function
Author(s) -
Mohammad Razia Sultana,
Memon Rabia,
Banday Anees,
Lokhandwala Mustafa
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06571
Subject(s) - oxidative stress , kidney , transcription factor , mitochondrion , activator (genetics) , kidney disease , sulforaphane , endocrinology , biology , keap1 , medicine , microbiology and biotechnology , gene , cancer research , genetics
Aging has a strong association with the development of kidney disease. About one in four women and one in five men, aged 65 years and above, have chronic kidney disease (CKD). Studies indicate compromised mitochondrial function in aging kidneys. However, the mechanisms of the decreased mitochondrial function in aging is unclear. The present study aims to investigate the mechanisms relating to the mitochondrial dysfunction in aging. The mechanisms thus explored will help us identify novel therapeutic targets to prevent or reverse kidney damage in elder individuals. Nuclear transcription factor Nrf2 is a cytosolic protein which when activated will translocate to the nucleus. After being translocated to the nucleus, it regulates the expression of genes involved in antioxidant and detoxification mechanisms. It binds to Antioxidant Response Element (ARE) on the gene promoters and increases the expression of genes that regulate the function of cells. We previously showed that Nrf2, was decreased in the kidneys of aged rats. Additionally, we also found a decrease in mitochondrial activity and kidney function. Therefore, we hypothesized that Nrf2 regulates kidney function via improving mitochondrial function during aging. We tested this hypothesis, by using Fischer344 rats, animal model of aging, and human kidney cells (HK2) in culture. Aged male Fischer 344 (F344) rats (20–24 months old) were divided into two groups. One group was treated with Nrf2 activator, sulforaphane (SF) [15mg/kg/day in drinking water for four weeks] and the other group (Control) was given drinking water alone. Nrf2 activation had significantly reduced the oxidative stress marker 8‐isoprostane levels in urine and increased urinary antioxidant capacity in the aged rats compared to their controls. The increased levels of protein in urine and plasma creatinine in aged animals were also reduced by sulforaphane treatment. Human kidney cells (HK2) were treated with sulforaphane (SF) at a dose of 20uM in the presence and absence of H 2 O 2 . H 2 O 2 treatment significantly reduced Nrf2 expression which was reversed by SF treatment. Also, the mitochondrial membrane potential improved in H 2 O 2 +SF treated cells as compared to H 2 O 2 treated cells. In conclusion, our results suggest that Nrf2 activation plays a key role in improving kidney function in aged rats. Support or Funding Information NIH Aging grant: AG057024‐01A1