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HIF/Prolyl‐4‐Hydroxlyase Domain (PHD) on Tubular and Vascular Renal Function following nitric oxide synthase inhibition
Author(s) -
Roberts Melvin,
Oyekan Adebayo
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.1131.13
Subject(s) - nitric oxide synthase , medicine , chemistry , nitric oxide , endocrinology , kidney , renal function , hypoxia (environmental) , oxygen , organic chemistry
PHD is an enzyme that degrades Hypoxia Inducible Factor alpha (HIFα), a transcription factor that activates protective genes during hypoxia. PHD, nitric oxide synthase (NOS) and heme oxygenase (HO) are expressed in the kidney and contribute to renal function. Hypoxia and NO inhibit normoxic PHD activity, accumulate HIF‐1α and enhanced renal function. However, PHD‐dependent renal function in the absence of NO is not known. We hypothesized that NO withdrawal will increase PHD activity and PHD inhibition will enhance renal responses upon NO withdrawal. Basal urine volume (UV) was 2.5 fold greater (P<0.05) in rats treated with dimethyloxalyll glycine (DMOG,), a PHD inhibitor. L‐NAME, a NOS inhibitor, increased UV (2.8 fold) and sodium excretion (2.8 fold, P<0.05) in control but not DMOG‐treated rats. DMOG increased GFR (2.9 fold; P<0.05) but LNAME decreased GFR in the control but not DMOG‐treated group. DMOG increased plasma bilirubin, index of HO activity, which increased more after LNAME. L‐NAME‐induced pressor response was greater in DMOG‐treated animals (P<0.05). Ang II (10–300 ng/kg) elicited dose‐dependent pressor responses which were greater (42±7%, P<0.05) in DMOG‐treated groups. These data suggest that PHD inhibition enhanced renal tubular function and accentuated pressor responses to AngII and NO withdrawal via mechanisms that appear to involve HO and NOS activities.