Beneficial effects of fenofibric acid on overexpression of extracellular matrix components, COX-2, and impairment of endothelial permeability associated with diabetic retinopathy
Section snippets
Background
FA is a lipid lowering drug that has been shown to be effective in reducing the risk of developing cardiovascular disease events (Keech et al., 2005). There is now consistent evidence from two major trials, the FA Intervention and Event Lowering in Diabetes (FIELD) study (Keech et al., 2007) and the Action to Control Cardiovascular Risk in Diabetes Eye (ACCORD-Eye) study (Chew et al., 2010) that FA reduces the risk of progression of diabetic retinopathy. In the FIELD study, which involved an
Cell culture – rat retinal endothelial cells
Rat retinal endothelial cells (RRECs) ascertained positive for von Willebrand factor were grown in Dulbecco's modified Eagle's medium (DMEM) with 10% FBS (Hyclon, Thermo Scientific, Waltham, MA), antibiotics, and antimycotics. Second to fourth passage cells were used in this study. All experiments were repeated at least four times. To examine the effect of FA on retinal vascular BM components, FN and Coll IV expression, and ZO-1 and COX-2 expression, RRECs were grown in normal medium (5 mmol/l
Fenofibric acid abrogates fibronectin and collagen IV overexpression induced by HG condition
Western blot analysis showed significantly increased FN protein expression in RRECs grown in HG medium when compared to those grown in normal medium (179 ± 23% of normal, p < 0.001, n = 6). When RRECs grown in HG medium were treated with FA, a significant reduction in FN protein level was observed compared to untreated RRECs grown in HG medium (132 ± 14% of normal vs. 179 ± 23% of normal, p = 0.001, n = 6) (Fig. 1A and B).
In parallel experiments, Western blot analysis showed significantly
Discussion
While substantial clinical benefits with FA on diabetic retinopathy were observed in the FIELD (Keech et al., 2007) and ACCORD-Eye studies (Chew et al., 2010), the underlying therapeutic mechanisms are not yet clear. In this study, we investigated the effect of FA on the inner BRB and how it may contribute to the maintenance of vascular integrity under HG condition. Our findings indicate that FA treatment prevents increased retinal endothelial cell monolayer permeability induced by the HG
Acknowledgments
Research was supported by National Institutes of Health/National Eye Institute Grants EY014702 and EY025528, and in part by a departmental grant from the Massachusetts Lions Organization (SR). In addition, this study was supported by grants from Ministerio de Ciencia y Tecnología (SAF2012-35562) and CIBER for Diabetes and Associated Metabolic Diseases (CIBERDEM). CIBERDEM is an initiative of the Instituto de Salud Carlos III. We acknowledge the assistance of Solvay Pharma S.A. in providing FA.
References (39)
- et al.
Fenofibrate improves age-related endothelial dysfunction in rat resistance arteries
Atherosclerosis
(2007) - et al.
Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin E2 secretion from diabetic rat retinas
Eur. J. Pharmacol.
(2004) - et al.
Renoprotective effects of fenofibrate in diabetic rats are achieved by suppressing kidney plasminogen activator inhibitor-1
Vasc. Pharmacol.
(2006) - et al.
Diabetic retinopathy
Lancet
(2010) - et al.
PPARalpha agonist fenofibrate protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress and MAPK activity
Biochem. Biophys. Res. Commun.
(2010) - et al.
Leukocyte-mediated endothelial cell injury and death in the diabetic retina
Am. J. Pathol.
(2001) - et al.
Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial
Lancet
(2007) - et al.
Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway
Exp. Eye Res.
(2007) - et al.
Fenofibrate for diabetic retinopathy
Lancet
(2007) - et al.
Inflammation in diabetic retinopathy
Prog. Retin. Eye Res.
(2011)
A study of capillary pericyte viability on extracellular matrix produced by endothelial cells in high glucose
Diabetologia
Pericyte adhesion is impaired on extracellular matrix produced by endothelial cells in high hexose concentrations
Diabetologia
Significance of COX-2 expression in human renal cell carcinoma cell lines
Int. J. Cancer
Therapeutic effects of PPARalpha agonists on diabetic retinopathy in type 1 diabetes models
Diabetes
Tight glycemic control regulates fibronectin expression and basement membrane thickening in retinal and glomerular capillaries of diabetic rats
Investig. Ophthalmol. Vis. Sci.
Effects of medical therapies on retinopathy progression in type 2 diabetes
N. Engl. J. Med.
Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats
Diabetes
Fenofibrate prevents the disruption of the outer blood retinal barrier through downregulation of NF-κB activity
Acta Diabetol.
Advanced glycation end products: sparking the development of diabetic vascular injury
Circulation
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2021, Progress in Retinal and Eye ResearchCitation Excerpt :Impaired cell-matrix interactions under HG condition have been shown to promote apoptosis (Beltramo et al., 2002). Studies suggest that HG altered cell-matrix interactions may compromise pericyte adhesion to the matrix, and thereby contribute to pericyte loss (Beltramo et al., 2002, 2003), and that overexpression of ECM components may play a critical role in HG or diabetes-induced apoptosis (Roy et al., 2011, 2015). Currently, it is unknown whether excess ECM synthesized by cells grown in HG mediates apoptotic cell death through modulation of integrin expression.
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2019, Drug Discovery TodayCitation Excerpt :Recent large-scale studies have shown that fenofibrate is able to stop the progression of DR [83–85]. Fenofibrate has been shown to downregulate the abnormal overexpression of basement membrane components and inflammatory mediators such as NF-κB and VEGF [86,87]. Fenofibrate can also reduce hyperglycaemia-induced oxidative stress in rat retinas and reduce the expression of thioredoxin-interacting protein (TXNIP) which is known to reduce cellular antioxidant capacity [88].
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2017, OphthalmologyCitation Excerpt :One might speculate that since the minority of patients had a complete absence of fluorescein leakage even after anti-VEGF therapy, some aspect of vessel permeability may be mediated by VEGF-independent pathways. A few studies have suggested that other signaling pathways such as angiopoietin-2,24 cyclooxygenase,25,26 and protein kinase Cζ27 may play a role in vessel leakage in DR. In the RIDE and RISE studies, 36 months of ranibizumab treatment was associated with long-term improvement of DR severity.13,14
Mechanistic Insights into Pathological Changes in the Diabetic Retina: Implications for Targeting Diabetic Retinopathy
2017, American Journal of PathologyCitation Excerpt :At high doses, cyclooxygenase-2 inhibitor meloxicam has been shown to reduce endothelial NO synthase concentrations,62 NF-κB activation levels,37 and leukocyte adhesion62 in diabetic retinas. In addition, our study indicates that fenofibrate can reduce high glucose-induced cyclooxygenase-2 up-regulation to exhibit anti-inflammatory effects.65 Aspirin has also been shown to significantly reduce the adhesiveness of leukocytes62 and, at high doses, to minimize the development of microvascular lesions in patients in non-proliferative DR.64,66,67
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2016, EBioMedicineCitation Excerpt :The mechanism(s) of this activation remains largely unknown. Retinal endothelial cell damage in diabetes (Joussen et al., 2001; Roy et al., 2015; Chronopoulos et al., 2011) is further confounded by inadequate vascular repair due, in part, to compromised function of the bone marrow (Busik et al., 2009; Caballero et al., 2007; Grant et al., 2002; Bhatwadekar et al., 2010; Chakravarthy et al., 2016). Bone marrow-derived circulating angiogenic cells (CACs) normally serve to mitigate endothelial injury, but are unable to participate in vascular repair in the retina of humans and rodents with chronic diabetes (Busik et al., 2009; Chakravarthy et al., 2016; Abu El-Asrar et al., 2011; Krady et al., 2005; Li Calzi et al., 2010; Tan et al., 2010; Liu et al., 2013; Sukmawati and Tanaka, 2015; Balaiya et al., 2014; Caballero et al., 2013).