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 (HIF-1), 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-1 and PHD are regulated and to what extent they contribute to the ensuing disorder.Method: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-1 expression, hypertension and renal injury.Results:In animals treated with N-G-nitro-l-arginine (L-NNA; 250mg/l in drinking water for 14 days) and high salt diet (4% NaCl), there was hypertension (415%, 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-1 (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-1 (31 +/- 5%, P<0.05) expression with no change in PHD1/2 expression or kidney and heart enlargement.Conclusion:These data suggest that the protective effect of physiological levels of nitric oxide may be by virtue of inhibition of PHD or increased HIF-1 expression, hence, the pathological changes produced following its withdrawal was accompanied by increased PHD or decreased HIF-1 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.