Abstract
Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, but the exact implications of altered NRF2 signaling on age-related renal mitochondrial impairment are not yet clear. Herein, we investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2–4 month) and aged (20–24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks. We observed significant impairment in renal cortical mitochondrial function along with perturbed redox homeostasis, decreased kidney function and marked impairment in NRF2 signaling in aged Fischer 344 rats. Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, an NRF2 repressor. Sulforaphane treatment did not affect the renal NRF2 expression or activity and mitochondrial function in young rats. Taken together, our results provide novel insights into the protective role of the NRF2 pathway in kidneys during aging and highlight the therapeutic potential of sulforaphane in mitigating kidney dysfunction in elders.
Highlights
Advancing age is a major contributing factor for the development of numerous chronic diseases, and kidneys are one of the vital organs affected, both structurally and functionally, by aging [1,2,3]
Animals were divided into four groups after acclimation; (1) Young control, young rats kept on tap water, (2) Aged control, aged rats kept on tap water, (3) Young+Sulforaphane, young rats administered with Nuclear factor erythroid 2–related factor 2 (NRF2) activator, sulforaphane, at a dose of 15mg/kg body weight/day in drinking water, and (4) Aged+Sulforaphane, aged rats administered with sulforaphane (15 mg/kg body weight/day)
Sulforaphane treatment significantly increased nuclear NRF2 protein expression (Figure 1C) but not total NRF2 expression in aged rats compared to aged control rats (Figure 1D)
Summary
Advancing age is a major contributing factor for the development of numerous chronic diseases, and kidneys are one of the vital organs affected, both structurally and functionally, by aging [1,2,3]. Comorbid conditions such as diabetes and hypertension can further exaggerate renal dysfunction and increase morbidity and mortality in elders [2,4]. Mitochondrial dysfunction and oxidative stress play a vital role in the pathophysiology of age-related kidney disease [10,11].
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