Increased Expression of NAD(P)H Oxidase Subunit p67phox in the Renal Medulla Contributes to Excess Oxidative Stress and Salt-Sensitive Hypertension

Abstract

SUMMARY NAD(P)H oxidase has been shown to be important in the development of salt-sensitive hypertension. Here we show that the expression of a subunit of NAD(P)H oxidase, p67phox, was increased in response to a high salt diet in the outer renal medulla of the Dahl salt-sensitive (SS) rat, an animal model for human salt-sensitive hypertension. The higher expression of p67phox, not the other subunits observed, was associated with higher NAD(P)H oxidase activity and salt-sensitivity in SS rats compared with a salt-resistant strain. Genetic mutations of the SS allele of p67phox were found in the promoter region and contributed to higher promoter activity than that of the salt-resistant strain. To verify the importance of p67phox, we disrupted p67phox in SS rats using zinc finger nucleases technology. These rats exhibited a significant reduction of salt-sensitive hypertension and renal medullary oxidative stress and injury. p67phox could represent a target for salt-sensitive hypertension therapy.

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“…28 Chromosome 13 contains several critical genes such as genes encoding renin and NADPH subunit p67 phox and several studies utilizing this model illustrate its critical role in BP regulation. [28][29][30][31][32][33] After 3 weeks on a HS diet, MAP was significantly lower in SS. 13 BN rats compared with SS rats, as Figure 1.…”

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“…Was the p67(phox) mutation described by Feng et al [10] present in the authors' strain? Would a positive-control experiment be possible?…”

“…However, not referenced or discussed in the current report is another important contribution from the Cowley laboratory. Feng et al reported that the expression of a particular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit, p67(phox), was increased in response to a high-salt diet in the renal medulla of the Dahl S rat [10]. The authors found a mutation in the promoter of the gene encoding p67(phox) that contributed to increased NADPH activity.…”