| Authors |
RamachandraRao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, Okada S, Shaw
MA, Sharma K
|
| Submitted By |
Kumar Sharma on 3/24/2010 |
| Status |
Published |
| Journal |
Journal of the American Society of Nephrology : JASN |
| Year |
2009 |
| Date Published |
8/1/2009 |
| Volume : Pages |
20(8) : 1765 - 1775 |
| PubMed Reference |
19578007 |
| Abstract |
Although several interventions slow the progression of diabetic nephropathy,
current therapies do not halt progression completely. Recent preclinical studies
suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the
mechanisms underlying its antifibrotic action are incompletely understood. Here,
we evaluated the role of PFD in regulation of the extracellular matrix. In mouse
mesangial cells, PFD decreased TGF-beta promoter activity, reduced TGF-beta
protein secretion, and inhibited TGF-beta-induced Smad2-phosphorylation, 3TP-lux
promoter activity, and generation of reactive oxygen species. To explore the
therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4
wk. PFD treatment significantly reduced mesangial matrix expansion and
expression of renal matrix genes but did not affect albuminuria. Using liquid
chromatography with subsequent electrospray ionization tandem mass spectrometry,
we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of
gene ontology and protein-protein interactions of these proteins suggested that
PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes
dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially
inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic
kidney disease and may exert its antifibrotic effects, in part, via inhibiting
RNA processing.
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