Pirfenidone is renoprotective in diabetic kidney disease.
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.

Investigators with authorship
Kumar SharmaUniversity of California San Diego


Tgfbr3transforming growth factor, beta receptor III