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Reduced Levels of Thyroid Receptor Interacting Protein 13 Prevents Recovery of Tubular Epithelial Cells following Renal Ischemia‐Reperfusion Injury
Author(s) -
Pressly Jeffrey D.,
Hama Taketsugu,
Regner Kevin R.,
Park Frank
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1217.11
Subject(s) - kidney , receptor , endocrinology , medicine , immunostaining , ischemia , medullary cavity , acute kidney injury , tunel assay , chemistry , immunohistochemistry
Damage to renal tubular epithelial cells by genetic, environmental, or biological insults can initiate complex signaling mechanisms that promote kidney repair and functional recovery. Recently, there is accumulating evidence that chromatin damage and the subsequent signaling repair mechanisms in the kidney can play a pivotal role in the recovery of the injured tubular epithelial cells following a biological stress. In this study, we demonstrate that thyroid receptor interacting protein 13 (TRIP13) is a critical modulator of tubular epithelial cell repair following ischemia‐reperfusion injury (IRI), a common type of renal stress. Transcript profiling demonstrated Trip13 mRNA to be robustly increased by 7.4 ± 0.3 (P<0.001; n=3) and 4.3 ± 2.0 (P<0.01; n=3) fold during the initial 24 and 72 hour period, respectively, following IRI. To further understand the role of TRIP13 in recovery to renal stress, unilateral ischemia‐reperfusion injury (IRI) was performed on Trip13 Gt/Gt hypomorphic mice. After 168 hours following the IRI procedure, the wild‐type Trip13 +/+ mice kidneys exhibited a significantly lower (P<0.05) number of damaged outer medullary renal tubules (38.7 ± 8.0%; n=5) compared to the hypomorph Trip13 Gt/Gt mouse kidneys (95.1 ± 1.4%; n=4). This effect was associated with a higher number of outer medullary collecting ducts as determined by AQP‐2 immunostaining in the WT (174 ± 16.7; n=5) than the hypomorph kidneys (69.0 ± 12.5; n=4). Histological analyses demonstrated significantly higher percentage of TUNEL‐positive cells, a marker of apoptosis, in the outer medulla by 2.4‐fold (P<0.05; n=3) in the Trip13 Gt/Gt mouse kidneys compared to the wild‐type Trip13 +/+ kidneys (n=6). This was also associated with significantly exaggerated levels of p53 and cleaved caspase‐7 by 45% and 170% (P<0.05), respectively, in Trip13 Gt/Gt mouse kidneys compared to Trip13 +/+ mouse kidneys (n=6). To evaluate whether inhibition of the p53 pathway could restore the tubular recovery following unilateral IRI, we performed a subsequent study in the presence of a p53 selective inhibitor, α‐pifithrin. Administration of α‐pifithrin in wild‐type Trip13 +/+ compared to hypomorphic Trip13 Gt/Gt kidneys resulted in a markedly reduced number of damaged outer medullary tubules (8.1 ± 0.6%; n=4 and 16.8 ± 1.1%; n=4, respectively) compared to their untreated control mouse kidneys (38.7 ± 8.0%; n=5 and 95.1 ± 1.4%; n=4, respectively). In all, this study suggests that insufficient TRIP13 levels increased the susceptibility of damaged renal tubular epithelial cells to progress towards cell death following ischemia‐reperfusion injury by exacerbating the p53 response pathway. Support or Funding Information This study was funded by NIH RO1‐DK90123, and UTHSC seed grant program.