Effect of pirfenidone against vanadate-induced kidney fibrosis in rats

Al-Bayati, Mohammed Ali; Xie, Yan; Mohr, Frederick C; Margolin, Solomon B.; Giri, Shri N.

doi:10.1016/s0006-2952(02)01213-3

Cited by 43 publications

(31 citation statements)

References 38 publications

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“…The presence of fibrosis in CKD is strongly related to the future manifestation of renal failure and has thus been related with poor long-term prognosis (24). Renal fibrosis is one of the consequences of kidney injury and is associated with renal dysfunction that may culminate in renal collapse (25,26). Renal fibrosis, particularly associated with glomerulosclerosis and renal interstitial fibrosis (5,10,27,28) that is characterised by tubular atrophy, tubular dilatation, increased fibrogenesis (29) and deposition of collagen and ECM (15), can progress in humans as a consequence of chronic infection, obstruction of the ureters, hypertension, diabetic nephropathy and chronic exposure to heavy metals (25).…”

Section: Impact Of Renal Fibrosis On Human Healthmentioning

confidence: 99%

“…In humans, failure of kidney function caused by fibrosis generally happens many years after the onset of diabetes or recurrent infections. Although it is not possible to reproduce this phase in animal studies, the use of animal models for renal fibrosis allows for the evaluation of drug efficacy in the treatment of renal fibrosis and also the pathogenesis of this disease (25). However, there are few or no drugs with the capacity to prevent the fibrotic process in experimental and human CKD (89), not only in monotherapy but also with a combination of therapies, perhaps because renal fibrosis is a complex process that involves several cell types and mediators (90).…”

Section: Effective Treatments and New Perspectives Of Researchmentioning

confidence: 99%

“…Despite the progress achieved in several studies with different types of treatments and drugs, no drugs presently exist for the effective treatment of renal fibrosis (25).…”

Section: Effective Treatments and New Perspectives Of Researchmentioning

confidence: 99%

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Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

2017

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Abstract. Chronic kidney disease (CKD) is a long-term condition in which theChronic kidney disease (CKD) represents a serious hazard to human health, and has a high prevalence. In developed countries, it is estimated that more than 10% of adults present some degree of CKD (1). Despite a varied initial evolution, which is related to the diversity of its aetiologies -namely genetics, autoimmune-related infections, environmental factors, diet, and drugs -progressive renal disease frequently results in renal fibrosis and finally in renal failure. The mechanisms implicated in renal fibrosis are still poorly understood, and existing therapies are ineffective or only slightly successful, hence it is essential to understand the pathophysiological mechanisms underlying the usual development of CKD, and to discover and better understand new strategies for treating this disease. In order to study the biopathology of this disease and to evaluate new treatments, animal models are required. The perfect animal model for renal disease research should have human-like renal anatomy, haemodynamics and physiology, as well as enabling the determination of relevant renal, biochemical and haemodynamic parameters. In all probability, no species can consistently meet all these requirements, and the experimental plan and other constraints often determine the choice of animal models for particular research applications. With this in mind, this review aims to describe and analyze animal models of renal fibrosis and suggest new areas of research. Renal Fibrosis: Aetiology and PathophysiologyDiabetes and hypertension are currently the two principal causes of CKD (2), among other causes such as infectious glomerulonephritis, renal vasculitis, ureteral obstruction, genetic alterations, autoimmune diseases (1) and drugs (3, 4). In general, diabetes causes glomerular hypertension by reducing the afferent arteriolar resistance while stimulating the efferent arterioles (2). Thus, elevated glomerular capillary pressure is one of the major factors in progressive renal sclerosis (5). Diabetes and hypertension gradually lead to glomerular expansion, which causes endothelial dysfunction and haemodynamic changes: loss of the glomerular basement membrane electric charge and its thickening, a decreased number of podocytes, foot-process effacement and mesangial distension have been shown to 1

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Section: Impact Of Renal Fibrosis On Human Healthmentioning

confidence: 99%

Section: Effective Treatments and New Perspectives Of Researchmentioning

confidence: 99%

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Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

2017

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“…It exhibits well-documented antifibrotic and anti-inflammatory properties in a variety of animal and in vitro models in different organs, including fibrosis of the lung, 17 kidneys, 18 heart, 19 liver, 20 and skin. 21 The exact molecular mechanism of action so far is unknown.…”

mentioning

confidence: 99%

Decreased Fibrogenesis After Treatment with Pirfenidone in a Newly Developed Mouse Model of Intestinal Fibrosis

Meier

Lutz

Cosín-Roger

et al. 2016

Inflammatory Bowel Diseases

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BACKGROUND Fibrosis as a common problem in patients with Crohn's disease is a result of an imbalance toward excessive tissue repair. At present, there is no specific treatment option. Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis with both antifibrotic and anti-inflammatory effects. We subsequently investigated the impact of pirfenidone treatment on development of fibrosis in a new mouse model of intestinal fibrosis. METHODS Small bowel resections from donor mice were transplanted subcutaneously into the neck of recipients. Animals received either pirfenidone (100 mg/kg, three times daily, orally) or vehicle. RESULTS After administration of pirfenidone, a significantly decreased collagen layer thickness was revealed as compared to vehicle (9.7 ± 1.0 versus 13.5 ± 1.5 µm, respectively, **P < 0.001). Transforming growth factor-and matrix metalloproteinase-9 were significantly decreased after treatment with pirfenidone as confirmed by real-time PCR (0.42 ± 0.13 versus 1.00 ± 0.21 and 0.46 ± 0.24 versus 1.00 ± 0.62 mRNA expression level relative to GAPDH, respectively, *P < 0.05). Significantly decreased transforming growth factor-after administration of pirfenidone was confirmed by Western blotting. CONCLUSION In our mouse model, intestinal fibrosis can be reliably induced and is developed within 7 days. Pirfenidone partially prevented the development of fibrosis, making it a potential treatment option against Crohn's disease-associated fibrosis.

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“…PFD has been considered as an antagonist of transforming growth factor β (TGFβ), and has anti-fibrotic, anti-inflammatory, and antioxidative stress activities (6, 12-14, 27, 36). PFD has demonstrated an anti-fibrotic effect via the downregulation of TGFβ expression in several animal nephropathy models, including unilateral ureteral obstruction (36), diabetic nephropathy (24,27), nephrectomy (35,38), vanadate-induced renal fibrosis (1), and calcineurin inhibitor-induced nephrotoxicity (5,6,34). In addition, the clinical effectiveness of PFD has been evaluated in human diabetic nephropathy (32) and focal segmental glomerulosclerosis (7).…”

mentioning

confidence: 99%

Renoprotective mechanisms of pirfenidone in hypertension-induced renal injury: through anti-fibrotic and anti-oxidative stress pathways

Naito

Weng

et al. 2013

Biomed. Res.

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Pirfenidone (PFD) is a novel anti-fibrotic agent that targets TGFβ. However, the mechanisms underlying its renoprotective properties in hypertension-induced renal injury are poorly understood. We investigated the renoprotective properties of PFD and clarified its renoprotective mechanisms in a rat hypertension-induced renal injury model. Dahl salt-sensitive rats were fed a high-salt diet with or without 1% PFD for 6 weeks. During the administration period, we examined the effects of PFD on blood pressure and renal function. After the administration, the protein levels of renal TGFβ, Smad2/3, TNFα, MMP9, TIMP1, and catalase were examined. In addition, total serum antioxidant activity was measured. Compared to untreated rats, PFD treatment significantly attenuated blood pressure and proteinuria. Histological study showed that PFD treatment improved renal fibrosis. PFD may exert its anti-fibrotic effects via the downregulation of TGFβ-Smad2/3 signaling, improvement of MMP9/TIMP1 balance, and suppression of fibroblast proliferation. PFD treatment also increased catalase expression and total serum antioxidant activity. In contrast, PFD treatment did not affect the expression of TNFα protein, macrophage or T-cell infiltration, or plasma interleukin 1β levels. PFD prevents renal injury via its anti-fibrotic and anti-oxidative stress mechanisms. Clarifying the renoprotective mechanisms of PFD will help improve treatment for chronic renal diseases.Pirfenidone (PFD; 5-methyl-1-phenylpyridin-2-one) is an anti-fibrotic agent. PFD has been considered as an antagonist of transforming growth factor β (TGFβ), and has anti-fibrotic, anti-inflammatory, and antioxidative stress activities (6, 12-14, 27, 36). PFD has demonstrated an anti-fibrotic effect via the downregulation of TGFβ expression in several animal nephropathy models, including unilateral ureteral obstruction (36), diabetic nephropathy (24, 27), nephrectomy (35, 38), vanadate-induced renal fibrosis (1), and calcineurin inhibitor-induced nephrotoxicity (5,6,34). In addition, the clinical effectiveness of PFD has been evaluated in human diabetic nephropathy (32) and focal segmental glomerulosclerosis (7). The anti-fibrotic effect of PFD might also be due to the regulation of the balance of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) (6,10,20,36). Furthermore, PFD may also exert its anti-fibrotic effect via the suppression of fibroblast proliferation (14). PFD has demonstrated anti-inflammatory effects via the inhibition of the expressions of inflammatory mediators such as tumor necrosis factor α (TNFα) and interleukin 1β (IL1β) both in vivo and vitro (2,

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Effect of pirfenidone against vanadate-induced kidney fibrosis in rats

Cited by 43 publications

References 38 publications

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

Decreased Fibrogenesis After Treatment with Pirfenidone in a Newly Developed Mouse Model of Intestinal Fibrosis

Renoprotective mechanisms of pirfenidone in hypertension-induced renal injury: through anti-fibrotic and anti-oxidative stress pathways

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