PMID- 18815219
OWN - NLM
STAT- MEDLINE
DCOM- 20090312
LR  - 20181113
IS  - 1931-857X (Print)
IS  - 1522-1466 (Electronic)
IS  - 1522-1466 (Linking)
VI  - 295
IP  - 6
DP  - 2008 Dec
TI  - p53 regulates renal expression of HIF-1alpha and pVHL under physiological 
      conditions and after ischemia-reperfusion injury.
PG  - F1666-77
LID - 10.1152/ajprenal.90304.2008 [doi]
AB  - Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) 
      and is characterized by widespread tubular and microvascular damage. The tumor 
      suppressor p53 is upregulated after IRI and contributes to renal injury in part 
      by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-alpha 
      conveys significant protection after IRI. The hypoxia-inducible factor-1 (HIF-1) 
      pathway is also activated after IRI and has opposing effects to those promoted by 
      p53. The balance between the HIF-1 and p53 responses can determine the outcome of 
      IRI. In this manuscript, we investigate whether p53 regulates the HIF-1 pathway 
      in a rodent model of IRI. HIF-1alpha is principally expressed in the collecting 
      tubules (CT) and thick ascending limbs (TAL) under physiological conditions. 
      However, inhibition of p53 with pifithrin-alpha increases the faint expression of 
      HIF-1alpha in proximal tubules (PT) under physiological conditions. Twenty-four 
      hours after IRI, HIF-1alpha expression is decreased in both CT and TAL. 
      HIF-1alpha expression in the PT is not significantly altered after IRI. Acute 
      inhibition of p53 significantly increases HIF-1alpha expression in the PT after 
      IRI. Additionally, pifithrin-alpha prevents the IRI-induced decrease in 
      HIF-1alpha in the CT and TAL. Parallel changes are observed in the HIF-1alpha 
      transcriptive target, carbonic anhydrase-9. Finally, inhibition of p53 prevents 
      the dramatic changes in Von Hippel-Lindau protein morphology and expression after 
      IRI. We conclude that activation of p53 after IRI mitigates the concomitant 
      activation of the protective HIF-1 pathway. Modulating the interactions between 
      the p53 and HIF-1 pathway can provide novel options in the treatment of AKI.
FAU - Sutton, Timothy A
AU  - Sutton TA
AD  - Div. of Nephrology, Dept. of Medicine, Indiana Univ. School of Medicine, 950 West 
      Walnut St., R-II, 202, Indianapolis, IN 46202, USA. tsutton2@iupui.edu
FAU - Wilkinson, Jared
AU  - Wilkinson J
FAU - Mang, Henry E
AU  - Mang HE
FAU - Knipe, Nicole L
AU  - Knipe NL
FAU - Plotkin, Zoya
AU  - Plotkin Z
FAU - Hosein, Maya
AU  - Hosein M
FAU - Zak, Katelyn
AU  - Zak K
FAU - Wittenborn, Jeremy
AU  - Wittenborn J
FAU - Dagher, Pierre C
AU  - Dagher PC
LA  - eng
GR  - DK-60,495/DK/NIDDK NIH HHS/United States
GR  - DK-79,312/DK/NIDDK NIH HHS/United States
GR  - R01 DK077124-02/DK/NIDDK NIH HHS/United States
GR  - DK-77,124/DK/NIDDK NIH HHS/United States
GR  - R01 DK077124/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080924
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Benzothiazoles)
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 3FPU23BG52 (Toluene)
RN  - D213B92S1Y (pifithrin)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
SB  - IM
MH  - Acute Kidney Injury/genetics/pathology/*physiopathology
MH  - Animals
MH  - Benzothiazoles/pharmacology
MH  - Cell Line
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*genetics
MH  - Kidney Cortex/physiopathology
MH  - Kidney Medulla/physiopathology
MH  - Kidney Tubules/physiopathology
MH  - Male
MH  - Microscopy, Confocal
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reperfusion Injury/genetics
MH  - Toluene/analogs & derivatives/pharmacology
MH  - Tumor Suppressor Protein p53/genetics/*physiology
MH  - Up-Regulation
MH  - Von Hippel-Lindau Tumor Suppressor Protein/*genetics
PMC - PMC2604829
EDAT- 2008/09/26 09:00
MHDA- 2009/03/13 09:00
PMCR- 2009/12/01
CRDT- 2008/09/26 09:00
PHST- 2008/09/26 09:00 [pubmed]
PHST- 2009/03/13 09:00 [medline]
PHST- 2008/09/26 09:00 [entrez]
PHST- 2009/12/01 00:00 [pmc-release]
AID - 90304.2008 [pii]
AID - F-90304-2008 [pii]
AID - 10.1152/ajprenal.90304.2008 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2008 Dec;295(6):F1666-77. doi: 
      10.1152/ajprenal.90304.2008. Epub 2008 Sep 24.