Increased expression of NAD(P)H oxidase subunit p67(phox) in the renal medulla contributes to excess oxidative stress and salt-sensitive hypertension.
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, p67(phox), 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 p67(phox), 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 p67(phox) were found in the promoter region and contributed to higher promoter activity than that of the salt-resistant strain. To verify the importance of p67(phox), we disrupted p67(phox) in SS rats using zinc-finger nucleases. These rats exhibited a significant reduction of salt-sensitive hypertension and renal medullary oxidative stress and injury. p67(phox) could represent a target for salt-sensitive hypertension therapy.
Physiology Department, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Di
D
Feng
Chun
C
Yang
Aron M
AM
Geurts
Terry
T
Kurth
Mingyu
M
Liang
Jozef
J
Lazar
David L
DL
Mattson
Paul M
PM
O'Connor
Allen W
AW
Cowley
D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism*; D007679:Kidney Medulla / Q000201:enzymology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D017931:DNA Primers; D010750:Phosphoproteins; C079789:neutrophil cytosol factor 67K