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Pirfenidone Is Renoprotective in Diabetic Kidney Disease

Satish P. RamachandraRao^*,,, Yanqing Zhu, Timothy Ravasi^,||, Tracy A. McGowan, Irene Toh, Stephen R. Dunn^,¶, Shinichi Okada^*,, Michael A. Shaw^** and Kumar Sharma^*,,

*Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, and
Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego,
^||Scripps NeuroAIDS Preclinical Studies Centre, and
Veterans Administration San Diego Healthcare System, La Jolla, California,
Center for Novel Therapies in Kidney Disease, Department of Medicine,
^¶Cancer Genomics Facility, Kimmel Cancer Center, and
**Proteomics and Mass Spectrometry Core Facility, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania

Correspondence: Dr. Satish P. RamachandraRao, Center for Renal Translational Medicine, Division of Nephrology and Hypertension, Department of Medicine, 407 Stein Clinical Research Building, Mail Box #0711, University of California, San Diego, La Jolla, CA 92093. Phone: 858-822-0875; Fax: 858-822-7483; E-mail: satishrao{at}ucsd.edu; or Dr. Kumar Sharma, Center for Renal Translational Medicine, Division of Nephrology and Hypertension, Department of Medicine, 406 Stein Clinical Research Building, Mail Box #0711, University of California, San Diego, La Jolla, CA 92093. Phone: 858-822-0860; Fax: 858-822-7483; E-mail: kusharma{at}ucsd.edu

Received for publication September 5, 2008. Accepted for publication April 1, 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-β promoter activity, reduced TGF-β protein secretion, and inhibited TGF-β–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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J. Am. Soc. Nephrol. 2009 20: A12. [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673