Published online before print April 6, 2009

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(American Journal of Pathology. 2009;174:1663-1674.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080687

HIF-Prolyl Hydroxylases in the Rat Kidney

Physiologic Expression Patterns and Regulation in Acute Kidney Injury

Johannes Schödel^*, Bernd Klanke^*, Alexander Weidemann^*, Björn Buchholz^*, Wanja Bernhardt^*, Marko Bertog, Kerstin Amann, Christoph Korbmacher, Michael Wiesener^*, Christina Warnecke^*, Armin Kurtz, Kai-Uwe Eckardt^* and Carsten Willam^*

From the Department of Nephrology and Hypertension,^* the Institute of Cellular and Molecular Physiology, and the Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen; and the Institute of Physiology, University of Regensburg, Regensburg, Germany

Hypoxia-inducible transcription factors (HIFs) play important roles in the response of the kidney to systemic and regional hypoxia. Degradation of HIFs is mediated by three oxygen-dependent HIF-prolyl hydroxylases (PHDs), which have partially overlapping characteristics. Although PHD inhibitors, which can induce HIFs in the presence of oxygen, are already in clinical development, little is known about the expression and regulation of these enzymes in the kidney. Therefore, we investigated the expression levels of the three PHDs in both isolated tubular cells and rat kidneys. All three PHDs were present in the kidney and were expressed predominantly in three different cell populations: (a) in distal convoluted tubules and collecting ducts (PHD1,2,3), (b) in glomerular podocytes (PHD1,3), and (c) in interstitial fibroblasts (PHD1,3). Higher levels of PHDs were found in tubular segments of the inner medulla where oxygen tensions are known to be physiologically low. PHD expression levels were unchanged in HIF-positive tubular and interstitial cells after induction by systemic hypoxia. In rat models of acute renal injury, changes in PHD expression levels were variable; while cisplatin and ischemia/reperfusion led to significant decreases in PHD2 and 3 expression levels, no changes were seen in a model of contrast media-induced nephropathy. These results implicate the non-uniform expression of HIF-regulating enzymes that modify the hypoxic response in the kidney under both regional and temporal conditions.

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