Hypoxia-Inducible Factor Prolyl-Hydroxylase 2 Senses High-Salt Intake to Increase Hypoxia Inducible Factor 1α Levels in the Renal Medulla

Abstract

High salt induces the expression of transcription factor hypoxia-inducible factor (HIF) 1α and its target genes in the renal medulla, which is an important renal adaptive mechanism to high-salt intake. HIF prolyl-hydroxylase domain-containing proteins (PHDs) have been identified as major enzymes to promote the degradation of HIF-1α. PHD2 is the predominant isoform of PHDs in the kidney and is primarily expressed in the renal medulla. The present study tested the hypothesis that PHD2 responds to high salt and mediates high-salt–induced increase in HIF-1α levels in the renal medulla. In normotensive rats, high-salt intake (4% NaCl, 10 days) significantly inhibited PHD2 expressions and enzyme activities in the renal medulla. Renal medullary overexpression of the PHD2 transgene significantly decreased HIF-1α levels. PHD2 transgene also blocked high-salt–induced activation of HIF-1α target genes heme oxygenase 1 and NO synthase 2 in the renal medulla. In Dahl salt-sensitive hypertensive rats, however, high-salt intake did not inhibit the expression and activities of PHD2 in the renal medulla. Correspondingly, renal medullary HIF-1α levels were not upregulated by high-salt intake in these rats. After transfection of PHD2 small hairpin RNA, HIF-1α and its target genes were significantly upregulated by high-salt intake in Dahl salt-sensitive rats. Overexpression of PHD2 transgene in the renal medulla impaired renal sodium excretion after salt loading. These data suggest that high-salt intake inhibits PHD2 in the renal medulla, thereby upregulating the HIF-1α expression. The lack of PHD-mediated response to high salt may represent a pathogenic mechanism producing salt-sensitive hypertension.