Renoprotective effects of pirfenidone on chronic renal allograft dysfunction by reducing renal interstitial fibrosis in a rat model
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).
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Cited by (9)
Alleviation of cardiac fibrosis using acellular peritoneal matrix-loaded pirfenidone nanodroplets after myocardial infarction in rats
2022, European Journal of PharmacologyCitation Excerpt :In 2008, pirfenidone was approved to treat idiopathic pulmonary fibrosis in Japan and was once classified as an orphan drug. After confirmation of its anti-pulmonary fibrotic effect (Ley et al., 2017; Kevin et al., 2018), it was also shown to inhibit fibrosis of multiple organs, including the kidney (Qiu et al., 2019), liver (Salah et al., 2019), and heart (Lewis et al., 2019) in a rat model. Pirfenidone's half-life is only 2.5 h after oral administration, and hence, a high dose is needed to achieve the desired therapeutic effect.
Pirfenidone is a renal protective drug: Mechanisms, signalling pathways, and preclinical evidence
2021, European Journal of PharmacologyCitation Excerpt :Further, Shihab et al. noted that PFD could suppress the expression of pro-apoptotic genes (p53 and fas-ligand) and down-regulate caspase 3 expression in the CsA-induced renal fibrosis model (Shihab et al., 2005), which demonstrates the anti-apoptotic ability of PFD. PFD has been evaluated in a variety of experimental models of primary and secondary kidney diseases, including 5/6 nephrectomised rats (Takakuta et al., 2010; Chen et al., 2013a; Shimizu et al., 1997; Chen et al., 2013b), FGS/Kist mouse (Park et al., 2003), streptozotocin-diabetic rats (Miric et al., 2001), db/db mice (RamachandraRao et al., 2009), hypertension-induced renal injury (Ji et al., 2013), UUO (Shimizu et al., 1998; Li et al., 2017), acute kidney injury due to bilateral renal ischemia (Lima-Posada et al., 2019), chronic renal allograft dysfunction (Qiu et al., 2019), and drug-induced renal fibrosis (Shihab et al., 2002, 2005; Brook et al., 2005; Al-Bayati et al., 2002; Sharawy and Serrya, 2020) (Table 1). Mechanical stress, oxidative stress, inflammation, and metabolic and vasoactive factors (such as high glucose level and activation of the renin-angiotensin-aldosterone system) can increase ROS production, mitochondrial damage and TGF-β expression, and impair kidney function in glomerular-related diseases, which may be alleviated by PFD (Fig. 1).
Acid-Base Balance Disorders During Kidney Preservation in Cold Ischemia
2020, Transplantation ProceedingsCitation Excerpt :It is difficult to analyze acidosis in separation from whole ischemia injury, in which short CIT changes are fully recoverable [29]. Longer CIT-associated negative factors result in local inflammation and fibrosis [31,32], but the origin of renal fibrosis in the allograft is complex and includes donor-related factors, in particular in case of expanded criteria donors, ischemia-reperfusion injury, immune-mediated damage, recurrence of underlying diseases, hypertensive damage, nephrotoxicity of immunosuppressants, recurrent graft infections, and postrenal obstruction, and so on [33,34], in which such a multifactorial analysis would require a considerably larger examined group. We found that kidney storage in cold ischemia is associated with organ acidosis independent of preservation method.
DIAGNOSTIC SIGNIFICANCE OF TGF-β1 IN KIDNEY RECIPIENTS WITH GRAFT DYSFUNCTION
2023, Vestnik Transplantologii i Iskusstvennykh OrganovHuangqi decoction (黄芪汤) attenuates renal interstitial fibrosis via transforming growth factor-β1/mitogen-activated protein kinase signaling pathways in 5/6 nephrectomy mice
2022, Journal of Traditional Chinese Medicine
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Zhen-Zhen Qiu, Ji-Ming He and Hao-Xiang Zhang have equal contribution.