Abstract 609: Hypoxia-inducible Factor (hif) Prolyl Hydroxylation Pathway In Hypertension And Renal End Organ Damage In Doca/salt Hypertension In The Rat
Kidney disease could result from hypertension and ischemia/hypoxia. Key mediators of cellular adaptation to hypoxia are oxygen-sensitive HIFs which are regulated by prolyl-4-hydroxylase domain (PHD)-containing dioxygenases. However, activation of HIF can be protective as in ischemic death but it can also promote renal fibrosis. Here we tested the hypotheses that HIF-1α expression will be increased concomitant with reduced PHD expression and PHD inhibition will exacerbate hypertension and target organ damage in DOCA/salt hypertension. In DOCA/salt hypertensive rats (DOCA 50 mg/kg s/c for 3 weeks+ 1% NaCl drinking water), HIF-1α expression was increased (2-fold; P<0.01) and PHD2 expression decreased (52+8%; P<0.05). PHD inhibition with DMAG or cobalt chloride which downregulated PHD mRNA and protein expression with no organ or blood pressure effect of their own, markedly attenuated hypertension (154+7 vs 123+7 mmHg; P<0.01), proteinuria (340+64 vs 116+14 mg/day; P<0.01), kidney or left ventricular hypertrophy (0.76+0.02 vs 0.68+0.03; P<0.05) induced by DOCA/1% NaCl treatment. Similarly, there was a marked blunting of tubular interstitial necrosis, fibrinoid changes and glomerular damage (P<0.01) in DOCA/salt hypertensive rats. Accompanying these changes was increased expression of TGFβ (2.5 fold; P<0.01) or KIM-1 (3.85+0.49 vs 2.67+0.83; P<0.01), marker of glomerular injury but reduced expression of nephrin and podocin (4.5 fold; P<0.01), markers of tubular injury in DOCA/salt hypertensive rats. PHD inhibition blunted these effects without affecting PHD2 expression. These data support a role for HIF/PHD pathway DOCA/salt hypertension as well as the protective effects of PHD inhibitors but casts doubt on the involvement of PHD per se as a therapeutic target in the hypertensive renal injury following DOCA/salt administration.
- © 2012 by American Heart Association, Inc.