title: The Role of Hypoxia-Inducible Factor/Prolyl Hydroxylation Pathway in Deoxycorticosterone Acetate/Salt Hypertension in the Rat.
abstract: KKidney disease could result from hypertension and ischemia/hypoxia. Key mediators of cellular adaptation to hypoxia are oxygen-sensitive hypoxia inducible factor (HIF)s which are regulated by prolyl-4-hydroxylase domain (PHD)-containing dioxygenases. However, HIF activation can be protective as in ischemic death or promote renal fibrosis in chronic conditions. This study tested the hypothesis that increased HIF-1α consequent to reduced PHD expression contributes to the attendant hypertension and target organ damage in deoxycorticosterone acetate (DOCA)/salt hypertension and that PHD inhibition ameliorates this effect. In rats made hypertensive by DOCA/salt treatment (DOCA 50 mg/kg s/c; 1% NaCl orally), PHD inhibition with dimethyl oxallyl glycine (DMOG) markedly attenuated hypertension (P<0.05), proteinuria (P<0.05) and attendant tubular interstitial changes and glomerular damage (P<0.05). Accompanying these changes, DMOG blunted the increased expression of kidney injury molecule (KIM)-1 (P<0.05), a marker of tubular injury and reversed the decreased expression of nephrin (P<0.05), a marker of glomerular injury. DMOG also decreased collagen I staining (P<0.05), increased serum nitrite (P<0.05) and decreased serum 8-isopostane (P<0.05). However, the increased HIF-1α expression (P<0.01) and decreased PHD2 expression (P<0.05) in DOCA/salt hypertensive rats was not affected by DMOG. These data suggest that reduced PHD2 expression with consequent increase in HIF-1α expression probably results from hypoxia induced by DOCA/salt treatment with the continued hypoxia and reduced PHD2 expression evoking hypertensive renal injury and collagen deposition at later stages. Moreover, a PHD inhibitor exerted a protective effect in DOCA/salt hypertension by mechanisms involving increased nitric oxide production and reduced production of reactive oxygen species.
authors.affiliation: Center for Cardiovascular Diseases, Texas Southern University, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Dallatu
authors.affiliation: Center for Cardiovascular Diseases, Texas Southern University, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nwokocha
authors.affiliation: Center for Cardiovascular Diseases, Texas Southern University, USA.
authors.forename: Ngozi
authors.initials: N
authors.lastname: Agu
authors.affiliation: Center for Cardiovascular Diseases, Texas Southern University, USA.
authors.forename: Choi
authors.initials: C
authors.lastname: Myung
authors.affiliation: College of Pharmacy, Chicago State University, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Newaz
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Garcia
authors.affiliation: Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, USA.
authors.forename: Luan D
authors.initials: LD
authors.lastname: Truong
authors.affiliation: Center for Cardiovascular Diseases, Texas Southern University, USA.
authors.forename: Adebayo O
authors.initials: AO
authors.lastname: Oyekan
keywords: Collagen I; DOCA hypertension; Hypoxia inducible factor (HIF); KIM-1; Nitric oxide; Prolyl-4-hydroxylase domain (PHD); Reactive oxygen species; ephrin