S.P. RamachandraRao, Y. Zhu, T. Ravasi, T.A. McGowan, I. Toh, S.R. Dunn, S. Okada, M.A. Shaw, K. Sharma
J Am Soc Nephrol., 20(8): 1765-1775, (2009)
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.