Pigment Epithelium-Derived Factor (PEDF) Receptors Are Involved in Survival of Retinal Neurons

Bürger, Susanne; Meng, Jie; Zwanzig, Annette; Beck, Mike; Pankonin, Maik; Wiedemann, Peter; Eichler, Wolfdietrich; Unterlauft, Jan Darius

doi:10.3390/ijms22010369

Cited by 17 publications

(14 citation statements)

References 45 publications

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“…We also investigated how deletion of the PEDF gene impacts expression of five putative PEDF-Rs, namely ATGL, LRP6, PLXDC1, PLXDC2, and LR, 18 , 19 , 22 , 23 which are important to the neurotrophic or antiangiogenic functions of PEDF. Our results showed that all five PEDF-R were expressed and transcribed at varying levels in the TG, LG, MG, and cornea.…”

Section: Resultsmentioning

confidence: 99%

“…The protein exerts its biological function by binding to one of several putative receptors. Adipose triglyceride lipase (ATGL), 19 low-density lipoprotein receptor–related protein 6 (LRP6) also known as Wnt coreceptor, 20 the plexin domain containing 1 (PLXDC1) and 2 (PLXDC2), 21 and the laminin receptor (LR) 22 , 23 have all been identified as putative receptors through which PEDF transduces its signals. There is growing evidence for PEDF as a therapeutic agent in various ophthalmic diseases including AMD, 24 diabetic retinopathy, 14 glaucoma, 25 and diabetic keratopathy, 26 mainly through its neurotrophic 44 amino acid domain (44-mer) 27 and antiangiogenic 34-mer.…”

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confidence: 99%

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PEDF Gene Deletion Disrupts Corneal Innervation and Ocular Surface Function

Shang

Liu

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Purpose The cornea is richly innervated by the trigeminal ganglion (TG) and its function supported by secretions from the adjacent lacrimal (LG) and meibomian glands (MG). In this study we examined how pigment epithelium–derived factor (PEDF) gene deletion affects the cornea structure and function. Methods We used PEDF hemizygous and homozygous knockout mice to study effects of PEDF deficiency on corneal innervation assessed by beta tubulin staining, mRNA expression of trophic factors, and PEDF receptors by adjacent supporting glands, corneal sensitivity measured using a Cochet-Bonnet esthesiometer, and tear production using phenol red cotton thread wetting. Results Loss of PEDF was accompanied by reduced corneal innervation and sensitivity, increased corneal surface injury and tear production, thinning of the corneal stroma and loss of stromal cells. PEDF mRNA was expressed in the cornea and its supporting tissues, the TG, LG, and MG. Deletion of one or both PEDF alleles resulted in decreased expression of essential trophic support in the TG, LG, and MG including nerve growth factor, brain-derived neurotrophic growth factor, and GDNF with significantly increased levels of NT-3 in the LG and decreased EGF expression in the cornea. Decreased transcription of the putative PEDF receptors, adipose triglyceride lipase, lipoprotein receptor–related protein 6, laminin receptor, PLXDC1, and PLXDC2 was also evident in the TG, LG and MG with the first three showing increased levels in corneas of the Pedf +/ − and Pedf − / − mice compared to wildtype controls. Constitutive inactivation of ERK1/2 and Akt was pronounced in the TG and cornea, although their protein levels were dramatically increased in Pedf − / − mice. Conclusions This study highlights an essential role for PEDF in corneal structure and function and confirms the reported rescue of exogenous PEDF treatment in corneal pathologies. The pleiotropic effects of PEDF deletion on multiple trophic factors, receptors and signaling molecules are strong indications that PEDF is a key coordinator of molecular mechanisms that maintain corneal function and could be exploited in therapeutic options for several ocular surface diseases.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

PEDF Gene Deletion Disrupts Corneal Innervation and Ocular Surface Function

Shang

Liu

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…Therefore, we consider that it is necessary to further explore the mechanism of the role of serine protease system in SCI. Furthermore, various anticoagulants (dabigatran, rivaroxaban, warfarin) are used for anticoagulation in the treatment of SCI, and some serine protease inhibitors (ulinastatin, neuroserpin, pigment epithelium-derived factor) have been shown to be neuroprotective [ 42 – 44 ], our study may provide guidance of administration time window selection for their future clinical application in SCI treatment.…”

Section: Discussionmentioning

confidence: 99%

Delayed administration of nafamostat mesylate inhibits thrombin-mediated blood–spinal cord barrier breakdown during acute spinal cord injury in rats

Zhao

Zhou

Zhao

et al. 2022

J Neuroinflammation

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Background Nafamostat mesylate (nafamostat, NM) is an FDA-approved serine protease inhibitor that exerts anti-neuroinflammation and neuroprotective effects following rat spinal cord injury (SCI). However, clinical translation of nafamostat has been limited by an unclear administration time window and mechanism of action. Methods Time to first dose of nafamostat administration was tested on rats after contusive SCI. The optimal time window of nafamostat was screened by evaluating hindlimb locomotion and electrophysiology. As nafamostat is a serine protease inhibitor known to target thrombin, we used argatroban (Arg), a thrombin-specific inhibitor, as a positive control in the time window experiments. Western blot and immunofluorescence of thrombin expression level and its enzymatic activity were assayed at different time points, as well its receptor, the protease activated receptor 1 (PAR1) and downstream protein matrix metalloproteinase-9 (MMP9). Blood–spinal cord barrier (BSCB) permeability leakage indicator Evans Blue and fibrinogen were analyzed along these time points. The infiltration of peripheral inflammatory cell was observed by immunofluorescence. Results The optimal administration time window of nafamostat was 2–12 h post-injury. Argatroban, the thrombin-specific inhibitor, had a similar pattern. Thrombin expression peaked at 12 h and returned to normal level at 7 days post-SCI. PAR1, the thrombin receptor, and MMP9 were significantly upregulated after SCI. The most significant increase of thrombin expression was detected in vascular endothelial cells (ECs). Nafamostat and argatroban significantly downregulated thrombin and MMP9 expression as well as thrombin activity in the spinal cord. Nafamostat inhibited thrombin enrichment in endothelial cells. Nafamostat administration at 2–12 h after SCI inhibited the leakage of Evans Blue in the epicenter and upregulated tight junction proteins (TJPs) expression. Nafamostat administration 8 h post-SCI effectively inhibited the infiltration of peripheral macrophages and neutrophils to the injury site. Conclusions Our study provides preclinical information of nafamostat about the administration time window of 2–12 h post-injury in contusive SCI. We revealed that nafamostat functions through inhibiting the thrombin-mediated BSCB breakdown and subsequent peripheral immune cells infiltration.

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“…What may cause the hyperresponsiveness of platelets? A possible cause of platelet hyperreactivity in patients with glaucoma may involve the pigment epithelium-derived factor (PEDF), which is a multifunctional secreted protein that mediates neuroprotection and inhibition of angiogenesis in the retina ( 21 ). PEDF is significantly reduced in glaucomatous eyes ( 22 ), which may lead to increased platelet aggregability and the establishment of a thrombogenic state.…”

Section: Discussionmentioning

confidence: 99%

Platelet Parameters and Their Relationships With the Thickness of the Retinal Nerve Fiber Layer and Ganglion Cell Complex in Primary Open-Angle Glaucoma

Shao

et al. 2022

Front. Neurol.

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ObjectiveGlaucoma is a neurodegenerative disease of the visual system. Platelet parameters are correlated with visual field mean deviation (MD) in glaucoma, but there is a lack of relative data on their relationship with structural changes in the retina. This study aimed to explore the relationship between platelet parameters and retinal nerve fiber layer (RNEL), ganglion cell complex (GCC) thickness, and cup/disk area ratio, evaluated by optical coherence tomography (OCT) in primary open-angle glaucoma (POAG).MethodsA total of 118 consecutive patients with POAG and 120 age- and sex-matched control subjects were included in this retrospective study. Demographic data, platelet parameters in blood tests, visual field, and OCT results were evaluated. The RNFL was divided into the temporal, superior, nasal, and inferior quadrants. Based on the visual field MD, the patients were stratified into mild (MD ≤ 6.0 dB), moderate (6 dB < MD ≤ 12 dB), and severe (MD > 12.0 dB) subgroups.ResultsPatients with POAG had significantly lower platelet (PLT) levels and significantly higher platelet distribution width (PDW) and mean platelet volume (MPV) levels than controls. As the visual field MD increased, structural evaluation by OCT identified loss of disk rim area, average GCC thickness, and average RNFL thickness (all P < 0.001), as well as increased PDW (P < 0.001) and MPV (P = 0.004) levels in patients with POAG. The Spearman's rank correlation analysis showed that PDW levels were significantly correlated with OCT parameters such as RNFL thickness (r = −0.370, P < 0.001), GCC thickness (r = −0.294, P = 0.001), and cup/disk area ratio (r = 0.322, P < 0.001), as well as visual field MD (r = 0.607, P < 0.001) and mean sensitivity (MS) (r = −0.570, P < 0.001). Significantly correlations were also found between MPV and RNFL thickness (r = −0.321, P < 0.001), GCC thickness (r = −0.194, P = 0.041), and cup/disk area ratio (r = 0.237, P = 0.010). All the quadrants showed similar negative correlations between PDW, MPV, and RNFL thickness. The multiple linear regression analyses showed significant association between PDW and RNFL thickness (β = −0.331, P < 0.001), PDW and GCC thickness (β = −0.288, P = 0.002), MPV and RNFL thickness (β = −0.313, P = 0.001), and MPV and GCC thickness (β = −0.188, P = 0.048).ConclusionThis study found significantly negative association between PDW, MPV levels and RNFL, GCC thickness, as well as positive association between PDW, MPV levels, and cup/disk area ratio in patients with POAG, suggesting that platelet activation may contribute to glaucomatous optic neuropathy.

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Pigment Epithelium-Derived Factor (PEDF) Receptors Are Involved in Survival of Retinal Neurons

Cited by 17 publications

References 45 publications

PEDF Gene Deletion Disrupts Corneal Innervation and Ocular Surface Function

PEDF Gene Deletion Disrupts Corneal Innervation and Ocular Surface Function

Delayed administration of nafamostat mesylate inhibits thrombin-mediated blood–spinal cord barrier breakdown during acute spinal cord injury in rats

Platelet Parameters and Their Relationships With the Thickness of the Retinal Nerve Fiber Layer and Ganglion Cell Complex in Primary Open-Angle Glaucoma

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