HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 292/1/F207    most recent 00457.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Li, N. Articles by Li, P.-L. Search for Related Content PubMed PubMed Citation Articles by Li, N. Articles by Li, P.-L.

Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia

Submitted 18 November 2005 ; accepted in final form 24 July 2006

Hypoxia inducible factor (HIF) prolyl-4-hydroxylase domain-containing proteins (PHDs) promote the degradation of HIF-1. Because HIF-1 is highly expressed in the renal medulla and HIF-1-targeted genes such as nitric oxide synthase, cyclooxygenase, and heme oxygenase are important in the regulation of renal medullary function, we hypothesized that PHD regulates HIF-1 levels in the renal medulla and, thereby, participates in the control of renal Na⁺ excretion. Using real-time RT-PCR, Western blot, and immunohistochemical analyses, we have demonstrated that all three isoforms of PHD, PHD1, PHD2, and PHD3, are expressed in the kidneys and that PHD2 is the most abundant isoform. Regionally, all PHDs exhibited much higher levels in renal medulla than cortex. A furosemide-induced increase in renal medullary tissue PO₂ significantly decreased PHD levels in renal medulla, whereas hypoxia significantly increased mRNA levels of PHDs in cultured renal medullary interstitial cells, indicating that O₂ regulates PHDs. Functionally, the PHD inhibitor L-mimosine (L-Mim, 50 mg·kg^–1·day^–1 ip for 2 wk) substantially upregulated HIF-1 expression in the kidneys, especially in the renal medulla, and remarkably enhanced (by >80%) the natriuretic response to renal perfusion pressure in Sprague-Dawley rats. Inhibition of HIF transcriptional activity by renal medullary transfection of HIF-1 decoy oligodeoxynucleotides attenuated L-Mim-induced enhancement of pressure natriuresis, which confirmed that HIF-1 mediated the effect of L-Mim. These results indicate that highly expressed PHDs in the renal medulla make an important contribution to the control of renal Na⁺ excretion through regulation of HIF-1 and its targeted genes.

fluid homeostasis; anoxia; natriuretic factor; gene transcription; renal tubules; renal hemodynamics

This article has been cited by other articles:

				C. Rosenberger, M. Goldfarb, A. Shina, S. Bachmann, U. Frei, K.-U. Eckardt, T. Schrader, S. Rosen, and S. N. Heyman Evidence for sustained renal hypoxia and transient hypoxia adaptation in experimental rhabdomyolysis-induced acute kidney injury Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1135 - 1143. [Abstract] [Full Text] [PDF]

				J. S. Pollock and P. K. Carmines Diabetic nephropathy: nitric oxide and renal medullary hypoxia Am J Physiol Renal Physiol, January 1, 2008; 294(1): F28 - F29. [Full Text] [PDF]