title: Antiproteinuric effect of pirfenidone in a rat model of anti-glomerular basement membrane glomerulonephritis.
abstract: While pirfenidone has been established as an effective anti-fibrosis remedy, whether or not its antifibrotic effect contributes to a reduction of proteinuria remains unclear. We investigated the renoprotective properties of pirfenidone in an anti-glomerular basement membrane (GBM) glomerulonephritis model both prophylactically and therapeutically to determine its profile against proteinuria. In the prophylactic regimen, pirfenidone was treated immediately after anti-serum injection. We observed a significant reduction in the progression of proteinuria (P<0.05) and decline in renal function (P<0.01) and also noted histological improvement in renal injury. These effects appeared to be due to the maintained expression of nephrin and podocin on podocytes as well as the reduced expression of profibrotic factors like transforming growth factor-β (TGF-β). The expression of nephrin mRNA was strongly negatively correlated with the amount of urinary protein excretion (R=-0.84, P<0.001), implicating podocyte damage in the outcome of proteinuria (R(2)=0.70). These results suggest that preservation of podocytes with the pirfenidone treatment may have resulted in the decrease of proteinuria. In contrast, when the therapeutic regimen was initiated 2 weeks after nephritis induction, pirfenidone had little effect on the progression of proteinuria, although the decline of renal function and fibrosis were suppressed. Taken together, present findings suggested that pirfenidone prevented the progression of proteinuria only when administered prophylactically but was still able to ameliorate the decline of renal function independent of proteinuria. In conclusion, pirfenidone as a prophylactic regimen reduces proteinuria in anti-GBM nephritis via preservation of podocytes with markedly reduced efficacy when administered as a therapeutic regimen.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: koji.takakura@astellas.com.
authors.forename: Koji
authors.initials: K
authors.lastname: Takakura
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mizukami
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Mitori
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noto
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D050533:Glomerular Basement Membrane / Q000187:drug effects* / Q000473:pathology; D005921:Glomerulonephritis / Q000652:urine*; D008297:Male; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000652:urine; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D011728:Pyridones; D012333:RNA, Messenger; D003404:Creatinine; C093844:pirfenidone
keywords: Glomerular injury; Pirfenidone; Podocyte; Proteinuria; Renal fibrosis