Shimizu T, Kuroda T, Hata S, Fukagawa M, Margolin S B, Kurokawa K
Shionogi Research Laboratories, Osaka, Japan. toshikatsu.shimizu@shionogi. co.jp
Kidney Int. 1998 Jul;54(1):99-109. doi: 10.1046/j.1523-1755.1998.00962.x.
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.
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.
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.
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.
吡非尼酮（PFD）是一种新型抗纤维化药物，实验和临床研究表明，它可以预防甚至逆转多个器官的细胞外基质积聚。单侧输尿管梗阻（UUO）是一种特征明确的实验性肾脏疾病模型，最终会导致肾小管间质纤维化。
给UUO大鼠或假手术大鼠在食物中给予PFD（500毫克/千克/天），持续21天，以检查对胶原蛋白产生的影响。在梗阻维持一周后解除梗阻，测量肾脏的肾功能，以检查PFD对肾功能障碍后恢复的影响。
用羟脯氨酸检测到的胶原蛋白含量在UUO大鼠肾脏中持续21天逐渐增加。给予PFD可显著抑制这些增加。PFD对假手术大鼠的胶原蛋白产生没有影响。UUO时，皮质中IV型和I型胶原蛋白以及基质金属蛋白酶-2的mRNA表达增加，但PFD治疗可抑制这种增加。皮质转化生长因子-β（TGF-β）mRNA水平在UUO大鼠中持续21天逐渐升高，但这种增加也可被PFD抑制。梗阻肾脏的菊粉清除率明显降低，解除梗阻后五周仍保持在低水平。尽管解除了梗阻，但在梗阻后肾脏中也观察到羟脯氨酸含量逐渐增加。解除梗阻后给予PFD不仅可减轻胶原蛋白积聚，还可诱导受损肾功能的恢复。
这些结果表明，在该模型中PFD可减轻肾纤维化和肾损伤，并提示PFD在临床上可能有助于预防进行性、不可逆的肾衰竭。
