Stabilization of hypoxia inducible factor-1a ameliorates acute renal neurogenic hypertension

作者：Koeners Maarten P; Vink Eva E; Kuijper Arno; Gadellaa Niels; Rosenberger Christian; Mathia Susanne; van den Meiracker Anton H; Garrelds Ingrid M; Blankestijn Peter J; Joles Jaap A^*

来源：Journal of Hypertension, 2014, 32(3): 587-597.

DOI：10.1097/HJH.0000000000000060

• acute neurogenic hypertension
• heme oxygenase 1
• hypoxia inducible factor 1 alpha
• kidney ischemia
• renal hemodynamics

Objectives:
Renal neurogenic hypertension (RNH) contributes to cardiovascular morbidity. Renal hypoxia may cause RNH and vice versa, leading to a vicious circle. Hypoxia adaptation is conferred through hypoxia-inducible factors (HIFs). We hypothesized that acute RNH is accompanied by increased renal vascular resistance (RVR) and that hypertension and increased RVR are countered by increasing HIF-1 alpha by cobalt chloride (CoCl2) preconditioning.
Methods:
First, we studied mean arterial pressure (MAP) and RVR in innervated or denervated contralateral kidneys in anesthetized rats before and after unilateral intrarenal injection of phenol, a manoeuvre known to elicit acute RNH. Then HIF alpha was induced by CoCl2 in drinking water (2mM, 10 days) after which we compared intrarenal isotonic saline or phenol injection on MAP and RVR in CoCl2 preconditioned and control rats. HIF-1 alpha was determined by immunohistochemistry.
Results:
Unilateral intrarenal phenol induced immediate rise in MAP and contralateral RVR, and comparable HIF-1 alpha upregulation in both kidneys, consistent with bi-renal hypoxia. Removing the phenol-injected kidney immediately normalized MAP. Contralateral renal denervation had no effect on the rise in MAP, but abrogated the contralateral increase in RVR, suggesting mediation by increased efferent nerve activity. Strong renal staining for HIF-1a confirmed efficacy of CoCl2 preconditioning, and time-dependent increase in heme oxygenase-1 gene expression stabilization of HIFa. CoCl2 preconditioning prior to phenol reduced both delta MAP (+10 +/- 2 vs. +20 +/- 3%, P=0.015) and delta RVR (+21 +/- 11 vs. +90 +/- 26%, P=0.003).
Conclusion:
Acute RNH leads to renal vasoconstriction and increased renal HIF-1 alpha. Increasing HIF-1 alpha by CoCl2 preconditioning ameliorates intrarenal phenol-induced RNH and renal vasoconstriction.

• 出版日期2014-3