Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2.

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.

Nrf2 inhibition induces oxidative stress, renal inflammation and hypertension in mice.

Oxidative stress and renal inflammation play a pivotal role in the pathogenesis of hypertension. The redox-sensitive transcription factor, nuclear factor E2-related factor 2 (Nrf2) is the master regulator of phase II antioxidant enzymes that protects against oxidative stress and inflammation. This study aimed to investigate the effect of Nrf2 inhibition on oxidative stress-associated hypertension and renal dopamine 1 receptor (D1R) dysfunction in mice. Male C57BL/6 J mice were treated with a pro-oxidant, L-buthionine sulfoximine (BSO) (10 mmol/L in drinking water), and ML385 (10 kg body weight/kg body weight/day, intraperitoneally), a novel Nrf2 inhibitor that blocks Nrf2 regulated downstream target genes expression. Mice treated with BSO exhibited oxidative stress, renal functional impairment, inflammation, and elevated blood pressure. Also, BSO treatment increased the activity of phase II antioxidant enzyme, NAD(P)H: quinone oxidoreductase-1 (NQO-1). BSO and ML385 co-treatment exhibited a robust increase in blood pressure, oxidative stress and intensified the renal function deterioration as indicated by a significant increase in serum creatinine, urinary albumin excretion rate, and albumin to creatinine ratio and decreased glomerular filtration rate (GFR). Also, BSO and ML385 co-treatment downregulated NQO-1 and significantly altered the inflammatory cytokines, IL-1ß and IL-10 levels. A D1R agonist SKF38393 failed to promote urinary sodium excretion indicating functional impairment in renal D1R. ML385 per se did not affect mean arterial pressure, GFR, and renal D1R function. Taken together, we concluded that the Nrf2 inhibition aggravated oxidative stress and inflammation by diminishing phase II antioxidant defense that deteriorates renal function and contributes to the development of hypertension in mice.