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Genetic regulation and functional relevance of the p67phox gene in salt‐sensitive hypertension
Author(s) -
Feng Di,
Yang Chun,
Lazar Jozef,
Mattson David,
OˈConnor Paul,
Cowley Allen W.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.874.1
Subject(s) - nadph oxidase , nad+ kinase , microbiology and biotechnology , allele , oxidase test , biology , medicine , chemistry , gene , endocrinology , biochemistry , enzyme , oxidative stress
A narrow region on rat Chr 13 was identified to harbor salt‐sensitive genes. p67 phox , a cytosolic subunit of NAD(P)H oxidase, is located in this region. We have previously found that on a high salt diet, the renal outer medulla (OM) of Dahl salt‐sensitive (SS) rats exhibited higher levels of p67 phox expression and NAD(P)H oxidase activity than salt‐resistant congenic rats that contain the p67 phox allele from the salt‐resistant Brown Norway rat. We generated the first p67 phox null mutant ( p67 phox −/−) SS rat in which we observed significantly reduced salt‐sensitive hypertension. In our present study, we sequenced a 1650 bp promoter region and found that the SS allele of p67 phox had a 204 bp deletion and four SNPs compared to the BN allele. The activity of the SS p67 phox promoter was 1.7 fold higher than that of the BN p67 phox promoter. We further characterized p67 phox − / − rats and showed that they had a 40% reduction in OM H 2 O 2 levels measured from interstitial fluid collected by microdialysis. Respiratory burst responses of peritoneal macrophages to phorbol 12‐myristate 13‐acetate were abolished in p67 phox − / − rats. p67 phox − / − rats also showed reduced renal injury, including reduced OM fibrosis, infiltrated T cells and macrophages, and glomerulosclerosis. These data provide new insights into the genetic regulation and functional relevance of p67 phox in salt‐sensitive hypertension. (HL‐82798; HL‐29587)