Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells.
The two hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that regulate the response to hypoxia. Recently, the factor inhibiting HIF (FIH1) was identified as a molecular oxygen-dependent dioxygenase that blunts the transcriptional activity of HIF and has also been implicated in HIF-dependent and -independent hypoxia responses. Interestingly, HIF accumulation in the kidney has been shown to confer renal protection and to also cause glomerular injury or enhance renal fibrosis. In order to better understand the regulation of hypoxia-inducible genes, we determined the expression of FIH1 in the kidney and its functional role in isolated renal cells. FIH1 was expressed only in distal tubules and in podocytes, thus showing a very distinct expression pattern, partially overlapping with sites of HIF-1α expression. In tubular cells, RNA silencing of FIH1 caused transcriptional activation of HIF target genes during hypoxia. In contrast, FIH1 silencing in podocytes enhanced transcription of hypoxia-inducible genes in an HIF-independent manner. Using the anti-Thy.1 rat model of glomerulonephritis, we found a gradual decrease of glomerular FIH1 expression during disease progression paralleled by an increase in hypoxia-inducible genes including CXCR4, a mediator of glomerular inflammation. Thus, FIH1 appears to be a suppressor of oxygen-dependent genes in the kidney, operating through HIF-dependent and -independent mechanisms.
Schödel
Johannes
J
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Bohr
Daniela
D
Klanke
Bernd
B
Schley
Gunnar
G
Schlötzer-Schrehardt
Ursula
U
Warnecke
Christina
C
Kurtz
Armin
A
Amann
Kerstin
K
Eckardt
Kai-Uwe
KU
Willam
Carsten
C
D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007518:Isoantibodies; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007518:Isoantibodies; D012333:RNA, Messenger; D012097:Repressor Proteins; C035678:anti-Thy antibody; D006899:Mixed Function Oxygenases; C551240:factor inhibiting hypoxia-inducible factor 1, mouse; C439790:HIF1AN protein, human; D010100:Oxygen