Acute Inactivation of the  VHL  Gene Contributes to Protective Effects of Ischemic Preconditioning in the Mouse Kidney

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Abstract

Background/Aims: The von Hippel-Lindau (VHL) protein functions as an E3 ubiquitin ligase, controlling the stability of hypoxia-inducible factor (HIF). Preinduction of HIF-1α before pathological insult activates a self-defense mechanism and suppresses further aggravation of organ or cellular injury by ischemia. We investigated whether acute inactivation of the VHL gene might play a role in the response of mice to ischemic renal injury. Methods: We generated tamoxifen-inducible conditional VHL knockout ( VHL-KO) mice to inactivate the VHL gene in an acute manner during renal ischemia-reperfusion injury (IRI) induced by bilateral clamping of kidney arteries. Renal IRI is characterized by renal dysfunction and tubular damage. Results: After the procedure of IRI, blood urea nitrogen (BUN) and creatinine (CRN) levels in control mice were significantly higher (BUN, 138.10 ± 13.03 mg/dl; CRN, 0.72 ± 0.16 mg/dl) than in VHL-KO mice (BUN, 52.12 ± 6.61 mg/dl; CRN, 0.24 ± 0.04 mg/dl; BUN: p < 0.05; CRN: p < 0.05). Histologically, tubular injury scores were higher in control mice than in VHL-KO mice (p < 0.05). Conclusion: We suggest that the acute inactivation of the VHL gene contributes to protective effects of ischemic preconditioning in renal tubules of the mouse.

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HIF-1alpha expression regulates the bactericidal capacity of phagocytes.

Carole Peyssonnaux, Vivekanand Datta, Thorsten Cramer … (2005)

Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. Here we report on our use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1, alpha subunit (HIF-1alpha) to myeloid cell innate immune function. HIF-1alpha was induced by bacterial infection, even under normoxia, and regulated the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNF-alpha. Mice lacking HIF-1alpha in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1alpha pathway through deletion of von Hippel-Lindau tumor-suppressor protein or pharmacologic inducers supported myeloid cell production of defense factors and improved bactericidal capacity. HIF-1alpha control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense.

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Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling.

Frank Gertler, William Kaelin, Nikola P Pavletich … (2002)

The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.

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Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway.

Norman Carroll, Margaret Ashcroft (2006)

Overexpression of hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1alpha versus HIF-2alpha to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1alpha and/or HIF-2alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1alpha and/or HIF-2alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1alpha and HIF-2alpha expression in hypoxia in these cells: HIF-2alpha siRNA enhanced HIF-1alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1alpha and HIF-2alpha due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2alpha protein expression and HIF-2alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically.

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Author and article information

Journal

Journal ID (publisher-id): NEE

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2008

Publication date (Print): November 2008

Publication date (Electronic): 27 October 2008

Volume: 110

Issue: 3

Pages: e82-e90

Affiliations

Departments of ^aPathology, ^bCardiovascular Control and ^cUrology, Kochi Medical School, Nankoku, Japan; ^dUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md., and ^eBasic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Md., USA

Article

Publisher ID: 166994 Other ID: Nephron Exp Nephrol 2008;110:e82

DOI: 10.1159/000166994

PMC ID: 2657226

PubMed ID: 18957870

SO-VID: 07d28f9d-5aad-4791-8f99-a520c767ee43

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 07 February 2008

Date accepted : 30 July 2008

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Figures: 4, References: 31, Pages: 1

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Acute Inactivation of the VHL Gene Contributes to Protective Effects of Ischemic Preconditioning in the Mouse Kidney

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Karger: Nephrology

Most cited references 21

HIF-1alpha expression regulates the bactericidal capacity of phagocytes.

Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling.

Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway.

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