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

Koeners, Maarten P.a; Vink, Eva E.a; Kuijper, Arnoa; Gadellaa, Nielsa; Rosenberger, Christianb; Mathia, Susanneb; van den Meiracker, Anton H.c; Garrelds, Ingrid M.c; Blankestijn, Peter J.a; Joles, Jaap A.a

doi: 10.1097/HJH.0000000000000060
ORIGINAL PAPERS: Neurogenic mechanisms

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-1α 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 HIFα was induced by CoCl2 in drinking water (2 mM, 10 days) after which we compared intrarenal isotonic saline or phenol injection on MAP and RVR in CoCl2 preconditioned and control rats. HIF-1α was determined by immunohistochemistry.

Results: Unilateral intrarenal phenol induced immediate rise in MAP and contralateral RVR, and comparable HIF-1α 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-1α confirmed efficacy of CoCl2 preconditioning, and time-dependent increase in heme oxygenase-1 gene expression stabilization of HIFα. CoCl2 preconditioning prior to phenol reduced both ΔMAP (+10 ± 2 vs. +20 ± 3%, P = 0.015) and ΔRVR (+21 ± 11 vs. +90 ± 26%, P = 0.003).

Conclusion: Acute RNH leads to renal vasoconstriction and increased renal HIF-1α. Increasing HIF-1α by CoCl2 preconditioning ameliorates intrarenal phenol-induced RNH and renal vasoconstriction.

aDepartment of Nephrology and Hypertension, University Medical Center Utrecht, the Netherlands

bCharité Universitaetsmedizin, Nephrology, Berlin, Germany

cDivision of Pharmacology, Department of Internal Medicine, Vascular and Metabolic Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands

Correspondence to Jaap A Joles, DVM, PhD, Department of Nephrology and Hypertension, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Tel: +31 30 253 5269; fax: +31 30 243 4932; e-mail:

Abbreviations: BSA, bovine serum albumin; CKD, chronic kidney disease; CoCl2, cobalt chloride; EPO, erythropoietin; GFR, glomerular filtration rate; HIF, hypoxia-inducible factor; HO-1, heme oxygenase 1; LK, left kidney; MAP, mean arterial pressure; PHD, HIF-prolyl hydroxylase; RBF, renal blood flow; RK, right kidney; RNH, renal neurogenic hypertension; RVR, renal vascular resistance

Received 18 July, 2013

Accepted 26 October, 2013

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins