HDAC dependent transcriptional repression of Bmp-7 potentiates TGF-ß mediated renal fibrosis in obstructive uropathy.
J Urol
; 191(1): 242-52, 2014 Jan.
Article
in En
| MEDLINE
| ID: mdl-23820056
ABSTRACT
PURPOSE:
Recombinant BMP-7 inhibits the pathogenesis of renal injury in response to various stimuli. However, little is known about the molecular regulation of endogenous BMP-7 and its renal protective functions. We examined transcriptional regulation of Bmp-7 and its role in the pathogenesis of renal injury resulting from urinary tract dysfunction. MATERIALS ANDMETHODS:
Obstruction induced renal injury was modeled in vivo in mice by unilateral ureteral obstruction and in vitro in primary kidney cells by treatment with transforming growth factor-ß, a profibrotic cytokine that is increased in the obstructed kidney.RESULTS:
Unilateral ureteral obstruction resulted in the loss of BMP-7 expression in conjunction with histone deacetylation and transcriptional repression of the Bmp-7 promoter. The histone deacetylase inhibitor trichostatin A stimulated Bmp-7 expression in primary kidney cells. Trichostatin A also inhibited the expression of transforming growth factor-ß dependent profibrotic genes in a manner that depended on BMP receptor signaling. These findings extended to the obstructed kidney in vivo, in which trichostatin A treatment restored the expression of Bmp-7 along with BMP-7 mediated suppression of transforming growth factor-ß dependent signaling pathways. Finally, trichostatin A stimulated activation of the BMP-7 pathway the ameliorated obstruction induced renal injury by preventing disruption of the renal architecture and the development of renal fibrosis.CONCLUSIONS:
These findings show that histone deacetylase dependent repression of Bmp-7 transcription is a critical event during the pathogenesis of renal injury in obstructive uropathy. Accordingly, treatment with histone deacetylase inhibitors represents a potentially effective strategy to restore BMP-7 expression and its renal protective functions during treatment of obstructive uropathy.Key words
BMP-7; COLIα1; ELISA; GAPDH; HDAC; IMCD; PCR; RT-PCR; SMA- and MAD-related protein; SMAD; TGF-ß; TSA; UUO; bone morphogenetic protein 7; bone morphogenic protein 7; enzyme-linked immunosorbent assay; fibrosis; glyceraldehyde-3-phosphate dehydrogenase; histone deacetylase; histone deacetylase inhibitors; inner medullary collecting duct; kidney; polymerase chain reaction; reverse transcriptase-PCR; transforming growth factor-ß; trichostatin A; type I collagen, α1 chain; unilateral ureteral obstruction; ureteral obstruction; α-SMA; α-smooth muscle actin
Full text:
1
Database:
MEDLINE
Main subject:
Ureteral Obstruction
/
Transforming Growth Factor beta
/
Bone Morphogenetic Protein 7
/
Histone Deacetylases
/
Kidney Diseases
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Urol
Year:
2014
Type:
Article