Elsevier

Life Sciences

Volume 233, 15 September 2019, 116666
Life Sciences

Renoprotective effects of pirfenidone on chronic renal allograft dysfunction by reducing renal interstitial fibrosis in a rat model

https://doi.org/10.1016/j.lfs.2019.116666Get rights and content

Abstract

Aim

Pirfenidone (PFD) has been used as medication for idiopathic pulmonary fibrosis due to its ability in reducing lung fibrosis. However, the underlying mode of action in renal fibrosis during chronic renal allograft dysfunction (CRAD) requires further investigation. Therefore, the present study was conducted to explore the effects of PFD on renal injury induced by CRAD.

Main methods

Initially, the CRAD rat model was established, followed by the intragastric administration of PFD to the rats. Urine and blood samples were collected and tested against indicators of renal functions. The renal tissues were microscopically observed to determine the changes in pathological morphology. The anti-inflammatory, anti-fibrotic and anti-oxidant properties of PFD were explored in the setting of CRAD.

Key findings

The success rate of model establishment was 92.31%, which was reflected by weight loss, appetite loss, faded fur, and retarded reaction, with the symptoms found to exacerbate with time. PFD treatment could improve renal function, ameliorate inflammation and renal fibrosis as well as promote the anti-oxidant ability of renal allograft, indicating its potential role as an effective therapeutic agent for CRAD.

Significance

In conclusion, PFD was found to have renoprotective effects on renal injury induced by CRAD, which resulted in the alleviation of inflammation and renal fibrosis, providing novelty for CRAD clinical treatment.

Introduction

In recent years, renal allograft transplant has been widely used as a promising treatment mode for chronic renal failure instead of dialysis since patients present with better prognosis and longer survival time [1]. However, the development of chronic renal allograft dysfunction (CRAD) is one of the major contributing factors affecting the survival of kidney transplant recipients [2]. CRAD can be attributed to injuries induced by immunological and non-immunological causes, characterized by pathological changes including tubular atrophy, fibrointimal hyperplasia, interstitial fibrosis, glomerulosclerosis and arteriolar hyalinosis [3]. Despite the application of effective immunosuppressants and sophisticated transplant techniques, long-term survival of renal allograft patients remains to be unsatisfactory [4]. Therefore, there is growing interest in developing novel therapeutic methods for the treatment of CRAD.

Pirfenidone (PFD) is an orally administered drug used for idiopathic pulmonary fibrosis to slow the progression of the disease in order to obtain well-functioning lungs, with a progression-free survival [5]. In addition to its immunosuppressive effects, PFD has also been characterized to have antifibrotic, antioxidant and anti-inflammatory properties [6]. In addition, there is evidence suggesting that PFD is a promising therapeutic agent for diabetic nephropathy with clinical features of inflammation and marked tubulointerstitial fibrosis [7]. More importantly, PFD could slow down the progression of renal fibrosis i.e. observable in renal diseases including chronic renal allograft injury, as reported in a previous study [8]. The renoprotective activity provided by this drug has also been documented in animal models and pathologies particularly against chronic renal failure, which was found to be through suppression of interstitial fibrosis [9]. Another study also demonstrated the ameliorative effects of PFD with inhibitory effects on mouse dendritic cell activation and function in both animal models and human patients after lung transplantation, highlighting its implication as potential therapy for restrictive allograft syndrome respectively [10,11]. Trials for clinical safety of PFD have also regarded its relative safe use for various demographics with chronic fibrotic disorders [12]. Given these literatures, the current study aims to investigate the cytoprotective effects of PFD in a uninephrectomized rat models in order to evaluate its use for CRAD treatment. This current study examined the effects of PFD on fibrosis, oxidation, and inflammation modulation, in order to provide a novel mechanism and scientific rationale for PFD mode of action to stabilize renal function during the treatment of CRAD.

Section snippets

Ethics statement

All laboratory animals were used for medical research and all procedures were approved by the Ethics Committee of Fuzhou General Hospital.

Model establishment

A total of 65 male congenic Lewis rats were used as kidney graft recipients while 85 Specific Pathogen Free congenic Fischer (F344) rats served as donors. All rats (200–250 g, Beijing Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) were housed in clean grade animal room. The CRAD models were established according to the method proposed by

The rat models of CRAD were successfully established

Initially, a rat model for CRAD was established. Compared with the rats in the normal group, there was no significant difference observed regarding the GFR of rats in the CRAD group at 0 d treatment post-administration (Fig. 1D), indicating the successful establishment of the rat models. The success rate was 92.31% out of the 65 rats that were initially enrolled in the study. Subsequently, the rats were randomly grouped into the CRAD, prednisone and PFD groups with 20 rats in each group. Rats

Discussion

CRAD is the predominant reason for the renal graft failure in the first decade following transplantation [1]. Fortunately, PFD has been found to have anti-inflammatory and anti-oxidative properties that could potentially alleviate such renal injury [21]. Furthermore, patients with idiopathic pulmonary fibrosis who received treatment with PFD were documented to have longer period of progression-free survival [22]. Thus, we conducted the present study with the main purpose of investigating the

Conclusions

Taken together, the findings from our study provide a better understanding on the renoprotective property of PFD using rat models of CRAD. The current work demonstrated that PFD has anti-fibrotic, anti-inflammatory, and anti-oxidant properties on renal tissues against CRAD following uninephrectomy surgery. Therefore, PFD might be a potentially new therapeutic option for CRAD. Nevertheless, the research is currently still in the preclinical stage, and the investigation on the detailed mode of

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This study was supported by Natural Science Foundation of Fujian Province (2017J01313) and National Natural Science Foundation of China (81473496).

References (34)

  • S. Assadiasl et al.

    Regulatory T cell subtypes and TGF-beta1 gene expression in chronic allograft dysfunction

    Iran. J. Immunol.

    (2014)
  • Q. Yan et al.

    Expression of GSK-3beta in renal allograft tissue and its significance in pathogenesis of chronic allograft dysfunction

    Diagn. Pathol.

    (2012)
  • T.E. King et al.

    A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis

    N. Engl. J. Med.

    (2014)
  • E.S. Kim et al.

    Pirfenidone: a review of its use in idiopathic pulmonary fibrosis

    Drugs

    (2015)
  • K. Sharma et al.

    Pirfenidone for diabetic nephropathy

    J. Am. Soc. Nephrol.

    (2011)
  • J.F. Chen et al.

    Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats

    Am. J. Physiol. Renal Physiol.

    (2013)
  • P. Bizargity et al.

    Inhibitory effects of pirfenidone on dendritic cells and lung allograft rejection

    Transplantation

    (2012)
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