Inhibition of prolyl hydroxylase domain-containing protein on hypertension/renal injury induced by high salt diet and nitric oxide withdrawal.

Background: Nitric oxide just as prolyl hydroxylase domain-containing protein (PHD) is a regulator of hypoxia inducible factor-1 α (HIF-1α), a transcription factor complex that controls the expression of most genes involved in hypoxia and cardiovascular diseases. In the absence of nitric oxide, it is not clear how HIF-1α and PHD are regulated and to what extent they contribute to the ensuing disorder.

Methods: Using the nitric oxide withdrawal/high salt diet model of hypertensive renal injury, this study tested the hypothesis that removal of the inhibition by nitric oxide on PHD predisposes to increased PHD but reduced HIF-1α expression, hypertension and renal injury.

Results: In animals treated with N-nitro-L-arginine (L-NNA; 250 mg/l in drinking water for 14 days) and high salt diet (4% NaCl), there was hypertension (41±5%, P<0.05), proteinuria (three-fold, P<0.05), kidney (22±3%, P<0.05) and heart enlargement (24±3%, P<0.05), as well as increased renal osteopontin (21±3%, P<0.05) and collagen IV (24±4%, P<0.05) expression. Accompanying these effects were increased expression of PHD1 (24±4%, P<0.05) and PHD2 (36±4%, P<0.05) but reduced HIF-1α (35±6%, P < 0.05) expression. Dimethyloxallyl glycine (5mg/kg), a PHD inhibitor, paradoxically exacerbated hypertension (46±7%, P<0.05), proteinuria (two-fold, P <0.05), and increased osteopontin (15±2%, P<0.05) and HIF-1α (31±5%, P<0.05) expression with no change in PHD1/2 expression or kidney and heart enlargement.

Conclusions: These data suggest that the protective effect of physiological levels of nitric oxide may be by virtue of inhibition of PHD or increased HIF-1α expression, hence, the pathological changes produced following its withdrawal was accompanied by increased PHD or decreased HIF-1α expression. Exacerbation of hypertension and renal injury following PHD inhibition suggests a deleterious effect in the chronic setting and challenges the dogma that inhibition of PHD is useful in cardiovascular diseases.