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Journal of Hypertension:
doi: 10.1097/HJH.0b013e32836356a0
ORIGINAL PAPERS: Kidney

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

Dallatu, Mohammad K.; Choi, Myung; Oyekan, Adebayo O.

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Abstract

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.

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-1α expression, hypertension and renal injury.

Results:

In animals treated with NG-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 (5 mg/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.

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-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.

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

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