Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model

Tomita, Yohei; Ozawa, Nobuhiro; Miwa, Yukihiro; Ishida, Ayako; Ohta, Michio; Kurihara, Toshihide

doi:10.3390/ijms20235878

Cited by 35 publications

(63 citation statements)

References 36 publications

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“…Several studies have shown that pemafibrate has therapeutic effects on retinal diseases [ 114 , 115 , 116 ]. Our group showed that oral administration of pemafibrate, but not fenofibrate, increased plasma fibroblast growth factor 21 (FGF21) levels in OIR and inhibited retinal neovascularization through the inhibition of HIF-1α and Vegfa expressions [ 115 ]. In addition, long-acting FGF21 inhibited HIF activity in a photoreceptor cell line under hypoxic conditions [ 115 ].…”

Section: Functions Of Spparmα In the Eyementioning

confidence: 99%

“…Our group showed that oral administration of pemafibrate, but not fenofibrate, increased plasma fibroblast growth factor 21 (FGF21) levels in OIR and inhibited retinal neovascularization through the inhibition of HIF-1α and Vegfa expressions [ 115 ]. In addition, long-acting FGF21 inhibited HIF activity in a photoreceptor cell line under hypoxic conditions [ 115 ]. Furthermore, we reported that oral administration of pemafibrate increased serum FGF21 levels in the streptozotocin-induced diabetic mouse model and preserved retinal function through maintaining the expression of synaptophysin which regulates synaptic vesicle endocytosis [ 114 ].…”

Section: Functions Of Spparmα In the Eyementioning

confidence: 99%

“…Additionally, long-acting FGF21 directly upregulated the expression of synaptophysin in differentiated neurons in vitro [ 114 ]. Interestingly, both studies have shown that pemafibrate did not increase the expression levels of FGF21 mRNA in the retina [ 114 , 115 ]. Therefore, pemafibrate could affect retinal diseases indirectly by upregulating systemic FGF21 levels to work on the damaged retina.…”

Section: Functions Of Spparmα In the Eyementioning

confidence: 99%

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PPARα Agonist Oral Therapy in Diabetic Retinopathy

2020

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Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.

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Section: Functions Of Spparmα In the Eyementioning

confidence: 99%

Section: Functions Of Spparmα In the Eyementioning

confidence: 99%

Section: Functions Of Spparmα In the Eyementioning

confidence: 99%

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PPARα Agonist Oral Therapy in Diabetic Retinopathy

2020

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“…Recently, several groups have shown that administration of a PPARα agonist increases fibroblast growth factor 21 (FGF21) [11,12]. A recent study shows that a selective PPARα modulator (SPPARMα) prevents pathological neovascularization in a mouse model by increasing circulating FGF21 [12]. FGF21 is a secreted protein that is comprised of 209 amino acids [13].…”

Section: Introductionmentioning

confidence: 99%

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

Tomita

Wang

et al. 2020

IJMS

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The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice were pre-treated with long-acting FGF21 analog or vehicle (Phosphate Buffered Saline; PBS) intraperitoneally (i.p.) before induction of retinal vascular leakage with intravitreal injection of mouse (m) vascular endothelial growth factor 164 (VEGF164) or PBS control. Five hours after mVEGF164 injection, we retro-orbitally injected Fluorescein isothiocyanate (FITC) -dextran and quantified fluorescence intensity as a readout of vascular leakage, using the Image Analysis Module with a machine learning algorithm. In FGF21-or vehicle-treated primary human retinal microvascular endothelial cells (HRMECs), cell permeability was induced with human (h) VEGF165 and evaluated using FITC-dextran and trans-endothelial electrical resistance (TEER). Western blots for tight junction markers were performed. Retinal vascular leakage in vivo was reduced in the FGF21 versus vehicletreated mice. In HRMECs in vitro, FGF21 versus vehicle prevented hVEGF-induced increase in cell permeability, identified with FITC-dextran. FGF21 significantly preserved TEER compared to hVEGF. Taken together, FGF21 regulates permeability through tight junctions; in particular, FGF21 increases Claudin-1 protein levels in hVEGF-induced HRMECs. Long-acting FGF21 may help reduce retinal vascular leakage in retinal disorders and machine learning assessment can help to standardize vascular leakage quantification.

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“…In addition to hypoxia and ROS, HIF-1α expression can be induced by numerous other factors, including nitric oxide (NO), in ammatory cytokines such as TNF-α, pro-in ammatory factors such as hormone-like growth factors such as TGF-β (5). As reported by some researches (6,7), HIF-1α expression may also be reduced by FGF21, a multifunctional factor with the protective effects on diabetic complications and energy hemostasis (8). VEGF is also up-regulated upon stimulation of such factors.…”

Section: Introductionmentioning

confidence: 99%

Effects of Securigera Securidaca Seed Extract, Alone and in combination with Glibenclamide, on Circulating Levels of Pro-Angiogenic/Anti-Angiogenic Biomarkers in Hyperglycemic Rats

Alizadeh-Fanalou

Babaei

Bahreini

2020

Preprint

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Background: Many diabetic patients use herbal medicines in addition to their mainstream treatments. Plants contain a well-known and unknown set of compounds that may exacerbate or improve diabetes complications. Thus, the side effects of these herbs should be known before prescribing. The aim of the study is to investigate the effects of hydroalcoholic extract of Securigera securidaca (L.) Degen & Dorfl (S. securidaca) seed (HESS) on angiogenesis/anti-angiogenesis balance in Streptozotocin (STZ)-induced diabetic rats, alone and in combination with glibenclamide. Methods: The groups involved in this animal study included diabetic and healthy control groups, groups treated with three doses of HESS, group treated with glibenclamide, and groups received combination therapy. Serum samples were taken and analyzed for the levels of angiogenic/ anti-angiogenic biomarkers.Results: Induction of diabetes increased serum levels of angiogenic agents and decreased circulating anti-angiogenic factors. The herbal extract, even with the highest dose, had little effects on the blood levels of the tested biomarkers except with TGF-β. Glibenclamide was more effective than the highest dose of HESS in preventing the increase in serum levels of angiogenic factors and in inhibiting the decrease in anti-angiogenic agents in diabetic rats. Combination therapy with the highest dose of HESS partly enhanced the glibenclamide effects.Conclusions: Although glibenclamide was more effective than the highest dose of HESS used in this study in preventing changes in serum concentrations of angiogenic/ anti-angiogenic biomarkers in the diabetic animals, this study show that S. securidaca has no side effects on diabetes complications caused by vascular disorders and neovascularization, and still it can be used as a herbal supplement with the standard drug.

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Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model

Cited by 35 publications

References 36 publications

PPARα Agonist Oral Therapy in Diabetic Retinopathy

PPARα Agonist Oral Therapy in Diabetic Retinopathy

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

Effects of Securigera Securidaca Seed Extract, Alone and in combination with Glibenclamide, on Circulating Levels of Pro-Angiogenic/Anti-Angiogenic Biomarkers in Hyperglycemic Rats

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