Abstract
The prevalence of hypertension increases with age. At the cellular level, oxidative stress is a major contributing factor to the pathogenesis of hypertension-induced kidney damage. The nicotinamide adenine dinucleotide phosphate (NADPH) family is one of the major sources of reactive oxygen species generation in the body. Although the isoform, NADPH oxidase 4 (Nox4) is highly expressed in the kidney, its role in kidney diseases remains controversial as both pathogenic and protective effects have been described. In addition, its role in hypertension-induced kidney damage in aging remains unexplored. Current evidence supports the involvement of epigenetics in oxidative stress. The aim of the present study was to investigate the role of Nox4 in Ang-II induced kidney damage in aged mice and the potential role for epigenetic regulation. Wild type (WT, C57BL/6J) mice aged 12-14 wk and 75-78 wk were used in this study and treated with Ang-II (1000 ng/kg/min) for 4 weeks. Control mice received saline infusion. Blood pressure (BP) was measured twice weekly. Aged mice exhibited higher mean BP than young mice after Ang-II treatment (135.76±4.8 vs. 118.7±12.28 mmHg) and decreased renal vascular density on barium angiography. Dihydroethidium staining revealed increased oxidative stress in hypertensive kidney of aged mice. In the aged kidney, protein expression of mitochondrial antioxidant enzymes, manganese superoxide dismutase and catalase was decreased by > 2-fold compared to young, and decreased further after Ang-II infusion. The renal sensors of energy and redox state, SIRT1 and SIRT3, showed similar decrease in aged kidney compared to young kidney in response to Ang-II. Nox4 and p22 phox protein expression was upregulated in the hypertensive kidneys of aged mice. The epigenetic mechanism involving DNA methylation showed increased DNA methyltransferases, DNMT1, 3a and 3b in the aged kidney. Following Ang-II, the aged kidney showed further increase of DNMT1 and 3a and a decrease in DNMT3b. Conclusion: Endogenous expression of Nox4 is upregulated in hypertensive kidney and is associated with alteration of DNA methyltransferases suggesting epigenetic regulation of oxidative stress in aged mice.
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