Pirfenidone improves renal function and fibrosis in the post-obstructed kidney.
BACKGROUND
Pirfenidone (PFD) is a novel anti-fibrotic agent that can prevent and even reverse extracellular matrix accumulation in several organs, as shown by experimental and clinical studies. Unilateral ureteral obstruction (UUO) is a well-characterized model of experimental renal disease culminating in tubulointerstitial fibrosis.


METHODS
UUO or sham-operated rats were administered PFD (500 mg/kg/day) in their food for 21 days to examine the effect on collagen production. The renal function was measured in the kidney after release of obstruction which had been maintained for one week to examine the effects of PFD on restoration after renal dysfunction.


RESULTS
The collagen content detected by hydroxyproline progressively increased in kidney with UUO for 21 days. These increases were significantly suppressed by administration of PFD. PFD had no effect on collagen production in sham-operated rats. Expression of mRNA for type IV and I collagen and matrix metalloproteinase-2 in the cortex increased with UUO, but was inhibited by PFD treatment. The levels of cortical transforming growth factor-beta (TGF-beta) mRNA progressively rose with UUO for 21 days, but this increase also could be suppressed by PFD. Inulin clearance of the obstructed kidney was markedly depressed and remained low at five weeks after release. A progressive increase in hydroxyproline content was also observed in the post-obstructed kidney despite the release of obstruction. Administration of PFD following the release not only attenuated collagen accumulation, but also induced recovery of the impaired renal function.


CONCLUSIONS
These results demonstrate that PFD can attenuate both renal fibrosis and renal damage in this model, and suggest that PFD can be clinically useful for preventing progressive, irreversible renal failure.
Shimizu
T
T
Shionogi Research Laboratories, Osaka, Japan. toshikatsu.shimizu@shionogi. co.jp
Kuroda
T
T
Hata
S
S
Fukagawa
M
M
Margolin
S B
SB
Kurokawa
K
K
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D018093:Gelatinases / Q000235:genetics; D006909:Hydroxyproline / Q000032:analysis; D007444:Inulin / Q000493:pharmacokinetics; D007672:Kidney Cortex / Q000737:chemistry / Q000201:enzymology; D007677:Kidney Function Tests; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D012337:RNA, Ribosomal, 18S / Q000032:analysis; D012339:RNA, Ribosomal, 28S / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics; D014513:Ureter / Q000601:surgery; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; D012339:RNA, Ribosomal, 28S; D016212:Transforming Growth Factor beta; D007444:Inulin; D003094:Collagen; C093844:pirfenidone; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D006909:Hydroxyproline