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Knocking out p67phox gene in the Dahl salt‐sensitive rat reduces salt‐sensitive hypertension and renal injury
Author(s) -
FENG DI,
Geurts Aron,
Kurth Terry,
Liang Mingyu,
Cowley Allen W.
Publication year - 2011
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.25.1_supplement.822.2
A congenic SS.13 BN26 inbred strain was developed with a 12.2Mb genomic region introgressed from the Brown Norway (BN) rat into chromosome 13 of the Dahl salt‐sensitive (SS) rat and was found to be protected against salt‐sensitive hypertension. Within the congenic substituted region, the p67 phox gene was identified which encodes for a cytosolic subunit of NAD(P)H oxidase. In renal outer medulla tissue (OM), we found this gene up‐regulated and NAD(P)H oxidase activity increased in the SS vs SS.13 BN26 rat after 7 days of 8% salt diet. To evaluate the functional relevance of this gene, we knocked out (KO) p67 phox on the SS background using zinc finger nuclease technology. Sequencing of these rats revealed a 5bp deletion in the coding region of the p67 phox gene. Mean arterial pressure (MAP) was measured by telemetry in 6 week old rats. MAP of the wild type littermates of the p67 phox KO rats rose from 103±4 (0.4% salt) to 175±9 mmHg after 14 days of 8.0% salt while the p67 −/− KO rats only increased from 103±2 to 145±8 mmHg (p<0.05). NAD(P)H oxidase activity was significantly reduced in the p67 −/− KO rats on day 14 of 8% salt diet and was associated with reduction of urinary microalbuminuria, proteinuria and outer medullary tubular cast (P<0.05). Together these results provide the first direct evidence of the importance of the p67 phox gene in the development of salt‐sensitive hypertension and renal injury in SS rats. (HL‐82798; HL‐29587)