HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury.
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.
Schödel
Johannes
J
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg,Erlangen, Germany.
Klanke
Bernd
B
Weidemann
Alexander
A
Buchholz
Björn
B
Bernhardt
Wanja
W
Bertog
Marko
M
Amann
Kerstin
K
Korbmacher
Christoph
C
Wiesener
Michael
M
Warnecke
Christina
C
Kurtz
Armin
A
Eckardt
Kai-Uwe
KU
Willam
Carsten
C
D058186:Acute Kidney Injury / Q000201:enzymology*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D015153:Blotting, Western; D002945:Cisplatin / Q000633:toxicity; D003287:Contrast Media / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000293:injuries; D007679:Kidney Medulla / Q000187:drug effects / Q000201:enzymology; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D003287:Contrast Media; D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; C102937:Uncx protein, rat; D011393:Procollagen-Proline Dioxygenase; C580731:Egln1 protein, rat; C087100:Egln3 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D002945:Cisplatin; D010100:Oxygen