HIF Prolyl Hydoxylases Sense High Salt to Increase HIF‐1α Levels in the Renal Medulla

It has been demonstrated that high salt induces the expression of hypoxia‐inducible factor (HIF)‐1α in the renal medulla, which is an important molecular mechanism for high salt adaptation in the kidney. However, it remains unclear how high salt intake induces increases in HIF‐1α level. HIF prolyl hydroxylase domain‐containing proteins (PHDs) have been identified as one of the critical regulators for HIF‐1α expression by promoting its degradation via proline hydroxylation, and these PHDs are highly expressed in the renal medulla. The present study was designed to test the hypothesis that PHDs respond to high salt intake and mediate the high salt‐induced increase in HIF‐1α levels in the renal medulla. In normotensive rats, high salt intake (4% NaCl, 2 weeks) significantly inhibited PHDs mRNA expressions as well as the enzyme activities in the renal medulla as detected by HIF‐1α peptide‐dependent conversion of [ 14 C]‐2‐oxoglutarate into succinate. Furthermore, renal medullary overexpression of PHD2 gene, a predominant isoform of PHDs in the kidney constructed into a pcDNA3 expression vector, significantly decreased HIF‐1α expression. In Dahl salt‐sensitive hypertensive rats, however, a high salt diet did not cause any change in the expression and activities of PHD in the renal medulla. Correspondingly, renal medullary HIF‐1α levels in these rats were not up‐regulated by a high salt diet. These data suggest that high salt intake inhibits PHD activity in the renal medulla and that decreased PHD activity protects HIF‐1α from being degraded, thereby upregulating the HIF‐1α expression. The lack of PHD‐mediated response to high salt may be one of major defects in salt‐sensitive individuals (supported by NIH grants HL 70726 and DK 054927).