Renoprotective properties of pirfenidone in subtotally nephrectomized rats

Takakuta, Koji; Fujimori, A.; Chikanishi, Toshihiro; Tanokura, Akira; Iwatsuki, Yoshiyuki; Yamamoto, Masanori; Nakajima, Hidenori; Okada, Masamichi; Itoh, Hiroyuki

doi:10.1016/j.ejphar.2009.12.011

Cited by 46 publications

(36 citation statements)

References 25 publications

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“…We found that pirfenidone significantly reduced expression of TGF-␤ 1 , ␣-SMA, CTGF, fibronectin, and FSP-1, which exhibit its antifibrotic properties. Previous studies also found that pirfenidone inhibit TGF-␤, collagen I/IV, and fibronectin expressions in the same animal model (35,36). However, its antifibrotic mechanisms are still not fully understood.…”

Section: Discussionmentioning

confidence: 95%

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats

Chen

Pan

et al. 2013

American Journal of Physiology-Renal Physiology

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Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease involved in the progression of renal fibrosis. Pirfenidone is a newly identified antifibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 wk. Twenty-four hour urinary protein, N-acetyl-␤-Dglycosaminidase (NAG) activity, systolic blood pressure, and C-reactive protein were determined. Paraffin-embedded sections were stained for CD68, CCR7, and CD163 macrophages. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1␣ (MIP-1␣), as well as M1 and M2 macrophages secretory markers, were evaluated by real-time RT-PCR and Western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including transforming growth factor-␤ 1, connective tissue growth factor, ␣-smooth muscle actin, fibronectin, and fibroblast-specific protein-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1␣ were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-␣, IL-6, and nitric oxide synthases-2 expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206, and CD86 expressed by M2 macrophages. Thus pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.

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Section: Discussionmentioning

confidence: 95%

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats

Chen

Pan

et al. 2013

American Journal of Physiology-Renal Physiology

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“…4.1 Beyond the line: revert fibrosis and its functional relevance in drug discovery Takakuta's pivotal paper on renoprotective properties of the antifibrotic agent pirfenidone [137] showed that delay of fibrosis improves kidney function in the subtotally nephrectomized rat model and was recently corroborated by an independent study using a totally different antifibrotic compound, the small-molecule antifibrotic drug, 3-methoxy-4-propargyloxycinnamoyl anthranilate (FT011, Fibrotech Therapeutics, Australia) [138]. In human, a similar pirfenidone renoprotective effect was observed in patients with diabetic nephropathy [139] and with focal segmental glomerulosclerosis [140], slowing the loss of GFR.…”

Section: Expert Opinionmentioning

confidence: 99%

New renal drug development to face chronic renal disease

Moll

Meier

Formentini

et al. 2014

Expert Opinion on Drug Discovery

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Currently, it is plausible to develop effective therapeutics for renal diseases with a plethora of approaches available for their development at a preclinical and clinical level. Furthermore, the relevance of biomarkers and the use of surrogate rare disease indications as proof of mechanism for faster and/or smaller clinical development are now possible; and these developments could revolutionize the way we treat renal disease in the future.

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“…TAKAKURA et al [49] demonstrated that prophylactic pirfenidone treatment (1% in feed) reduced the increase in area staining positive for fibrosis by ,80% with trends toward improvement of proteinuria as well as creatinine and blood urea nitrogen levels (table 1 and online supplementary material). SHIMIZU et al [50] also evaluated the effect of pirfenidone in the 5/6 nephrectomy model.…”

Section: Effects In Models Of Renal Fibrosismentioning

confidence: 99%

“…Many of the cellular and molecular mediators of renal fibrosis are common to fibrosis in other organs including the presence of persistent fibroblasts and myofibroblasts, elevated fibrogenic mediators (TGF-b, PDGF, interleukin (IL)-1b and basic (b)FGF), and an imbalance of metalloproteinases and their inhibitors [63]. The effect of pirfenidone in reducing renal fibrosis has been established in a several studies, including models driven by partial nephrectomy [49,50], unilateral ureteral obstruction (UUO) [48], diabetic nephropathy [51], cyclosporine [64,65] and vanadate [66]. A limited subset of these studies is summarised below.…”

Section: Effects In Models Of Renal Fibrosismentioning

confidence: 99%

Antifibrotic activities of pirfenidone in animal models

Schaefer¹,

Ruhrmund²,

Lin³

et al. 2011

Eur Respir Rev

390

287

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Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-b. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component. KEYWORDS: Animal model, antifibrotic, fibrosis, idiopathic pulmonary fibrosis, pirfenidone F ibrosis, the dysregulated deposition of extracellular matrix (ECM) with progressive destruction of normal tissue, is a primary or contributing factor in chronic disease states in several organs. Pulmonary fibrosis is associated with numerous diffuse parenchymal lung diseases, of which the most common are idiopathic pulmonary fibrosis (IPF) and sarcoidosis [1]. Cardiac fibrosis is associated with chronic heart failure, atrial fibrillation, and cardiac remodelling following acute myocardial infarction [2,3]. Renal fibrosis is associated with multiple forms of chronic kidney disease and correlates with impairment of kidney function [4,5]. Hepatic fibrosis is associated with chronic hepatitis B and C viral infections and nonalcoholic steatohepatitis [6]. Each of these conditions represents a significant unmet medical need, warranting significant research and clinical study into treatment for fibrotic disease.Pirfenidone (Esbriet1, Pirespa1) is an orally active small molecule comprising a modified phenyl pyridone ( fig. 1). The compound exhibits well documented antifibrotic and anti-inflammatory activities in a variety of animal and cellbased models, although its molecular target has not been elucidated. Pirfenidone was initially identified as having anti-inflammatory activity in animal models and evaluated for use as an antiinflammatory drug [7,8]. However, the unexpected identification of antifibrotic effects in animals treated with pirfenidone redefined the interest in the compound [9]. Subsequently, pirfenidone has been shown to attenuate fibrosis in numerous animal models, including fibrosis of the lung, liver, heart and kidney.The most extensive clinical studies of pirfenidone are for treatment of IPF, a chronic interstitial lung disease characterised by the unregulated deposition of ECM leading to the unremitting destruction of normal lung. Patients diagnosed with IPF typically experience progressive pulmonary insufficiency, and most die of respiratory failure. The estimated median survival upon diagnosis is approximately ...

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Renoprotective properties of pirfenidone in subtotally nephrectomized rats

Cited by 46 publications

References 25 publications

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats

New renal drug development to face chronic renal disease

Antifibrotic activities of pirfenidone in animal models

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