As the aqueous humor leaves the eye, it first passes through the trabecular meshwork (TM). Increased flow resistance in this region causes elevation of intraocular pressure (IOP), which leads to the occurrence of ...As the aqueous humor leaves the eye, it first passes through the trabecular meshwork (TM). Increased flow resistance in this region causes elevation of intraocular pressure (IOP), which leads to the occurrence of glaucoma. To quantitatively evaluate the effect of high IOP on the configuration and hydraulic permeability of the TM, second harmonic generation (SHG) microscopy was used to image the microstructures of the TM and adjacent tissues in control (normal) and high IOP conditions. Enucleated rabbit eyes were perfused at a pressure of 60 mmHg to achieve the high lOP. Through the anterior chamber of the eye, in situ images were obtained from different depths beneath the surface of the TM. Porosity and specific surface area of the TM in control and high IOP conditions were then calculated to estimate the effect of the high pressure on the permeability of tissue in different depths. We further photographed the histological sections of the TM and compared the in situ images. The following results were obtained in the control condition, where the region of depth was less than 55 μm with crossed branching beams and large pores in the superficial TM. The deeper meshwork is a silk-like tissue with abundant fluorescence separating the small size of pores. The total thickness of pathway tissues composed of TM and juxtacanalicular (JCT) is more than 100 p.m. After putting a high pressure on the inner wall of the eye, the TM region progressively collapses and decreases to be less than 40 μm. Fibers of the TM became dense, and the porosity at 34 μm in the high IOP condition is comparable to that at 105 μm in the control condition. As a consequent result, the permeability of the superficial TM decreases rapidly from 120 μm2 to 49.6 μm2 and that of deeper TM decreases from 1.66 μm2 to 0.57 μm2. Heterogeneity reflected by descent in permeability reduces from 12.4 μm of the control condition to 3.74 μm of the high IOP condition. The persistently high IOP makes the TM region collapse from its normal state, in which the collagen fibers of the TM are arranged in regular to maintain the physiological permeability of the outflow pathway. In the scope of pathologically high IOP, the microstructure of the TM is sensitive to pressure and hydraulic permeability can be significantly affected by IOP.展开更多
AIM:To observe the changes in Schlemm’s canal(SC),trabecular meshwork(TM),and anterior chamber relevant parameters after small incision lenticule extraction(SMILE) of myopia patients.METHODS:A total of 58 eyes from 3...AIM:To observe the changes in Schlemm’s canal(SC),trabecular meshwork(TM),and anterior chamber relevant parameters after small incision lenticule extraction(SMILE) of myopia patients.METHODS:A total of 58 eyes from 30 patients who underwent SMILE were divided into a low and moderate myopia group(group A,32 eyes) and a high myopia group(group B,26 eyes).The diameter and area of the SC,the width and thickness of TM obtained by CIRRUS HD-OCT5000,and the related anterior chamber parameters obtained by Pentacam anterior segment analysis system,accommodation amplitude(AMP) were observed pre-and postoperatively.The preoperative intraocular pressure(IOP) and postoperative correction of intraocular pressure(IOPcc) were measured.RESULTS:The diameter and area of the SC in the two groups were significantly increased postoperatively(all P<0.01).The TM width of the patients in the two groups were increased at 1mo after surgery(both P<0.01),but the TM thickness did not change(P>0.05).The corneal curvature,central anterior chamber depth,and anterior chamber volume decreased after SMILE surgery(all P<0.01).There was a weak negative correlation between the SC area change and AMP change in group A(r=-0.362,P<0.01).The postoperative IOP decreased after correction by Shah formula(P<0.05).CONCLUSION:SC and TM in myopia patients change in the early postoperative stage of SMILE and the IOP is decline.展开更多
AIM: To investigate changes in extracellular matrix(ECM) gene expression in human trabecular meshwork(HTM) cells in response to mechanical fluid flow stimulation.METHODS: HTM cells were grown on a glass plate coated w...AIM: To investigate changes in extracellular matrix(ECM) gene expression in human trabecular meshwork(HTM) cells in response to mechanical fluid flow stimulation.METHODS: HTM cells were grown on a glass plate coated with 0.02% type Ⅰ collagen(COL) and exposed to shear stress(0, 0.2, 1.0 dyne/cm;) for 12 h.Changes in genes related to the ECM were evaluated by real-time reverse transcriptase-polymerase chain reaction.Phosphorylation of Smad2 protein was investigated by Western blotting.RESULTS: After mechanical stimulation, COL type 4 alpha 2, COL type 6 alpha 1, and fibronectin-1 mRNA were significantly higher than the static control(P<0.05, <0.05, and <0.01, respectively).The metalloproteinase-2 and plasminogen activator inhibitor-1 mRNA were significantly higher than the static control(P<0.05 and <0.01, respectively), while the differences in the tissue inhibitors of metalloproteinases-2 mRNA were not significant.The phosphorylation of Smad2 levels was significantly higher compared to the static control cells.CONCLUSION: Changes in the expressions of genes associated ECM metabolism result in HTM cells after mechanical stimulation.The mechanical stimulation of the aqueous humor to the trabecular meshwork may promote ECM turnover and contribute to intraocular pressure homeostasis.展开更多
Background Trabecular meshwork (TM) cell volume may be an important determinant of aqueous humor outflow in the eye. This study aimed to evaluate the role of Hepll domain peptides V on corneal permeability, corneal ...Background Trabecular meshwork (TM) cell volume may be an important determinant of aqueous humor outflow in the eye. This study aimed to evaluate the role of Hepll domain peptides V on corneal permeability, corneal endothelial cells, intraocular pressure (lOP) and morphology of trabecular meshwork in rats. Methods The lOP of rat eyes was measured before and 3, 5, 7 and 8 hours after topical delivery of Hepll domain peptides V through intracameral injections. The peptide's concentration in aqueous humor was assessed by high performance liquid chromatography (HPLC). The shape and density of endothelial cells were observed by laser confocal microscopy 8 hours, 3 and 14 days after intracameral injections of Hepll domain peptides V. The morphological changes in TM of rat eyes were assessed by transmission electron microscopy (TEM). Results Intracameral injection of Hepll domain peptides V significantly (P 〈0.001) decreased lOP by (5.71±2.10) mmHg in rats at 5 hours after injection. There were no obvious changes of the shape and the density of corneal endothelial cells. In addition, morphological changes in the TM of rats were observed including the expansion of intercellular spaces in the juxtacanalicular meshwork, removal of extracellular material, cellular relaxation, and cytoskeleton reorganization. Conclusions Hepll domain peptides V could not penetrate cornea and was safe to corneal endothelial cells. Hepll domain peptides V could significantly decrease lOP in rat probably by disorganizing actin cytoskeleton and cell-junction in the TM.展开更多
Purpose:To investigate the anterior segment in nanophthalmic eyes and their association with intraocular pressure after cataract surgery.Methods:Thirty-two nanophthalmic eyes(axial length[AL]<18.5 mm)in 18 patients...Purpose:To investigate the anterior segment in nanophthalmic eyes and their association with intraocular pressure after cataract surgery.Methods:Thirty-two nanophthalmic eyes(axial length[AL]<18.5 mm)in 18 patients and 35 normal eyes(21.0≤AL≤24.5 mm)in 35 controls who had undergone uneventful cataract surgery were included.Swept-source optical coherence tomography was used to compare the anterior segment structures between the two groups.The associations between the anterior segment characteristics of nanophthalmic eyes and postoperative intraocular pressure(IOP)were also investigated.Results:The IOP-lowering effect of cataract surgery was remarkably insufficient in nanophthalmic eyes.Peripheral anterior synechiae(PAS)were observed in 56%(18/32)of nanophthalmic eyes,and a characteristic boomerangshaped iris was observed in 28%(9/32).The anterior surface of the iris seemed"smoother"in nanophthalmic eyes than in normal eyes.Schlemm's canal(SC)diameter,SC area,trabecular meshwork(TM)thickness,TM width,and TM area were generally smaller in the nanophthalmic eyes.Younger age,higher preoperative IOP,broader PAS,and smaller SC area were main contributors to higher postoperative IOP.AL and SC diameter may also be of great importance in IOP prediction in patients without glaucoma surgery and PAS.Conclusions:The morphological features of the anterior segment in nanophthalmic eyes are significantly different from those of normal eyes.Influencing factors such as age,AL,preoperative IOP,extent of PAS,SC and TM size could all be prognostic for IOP after cataract surgery in nanophthalmic eyes.Trial registration:ClinicalTrails.gov,Trial registration number:NCT02182921,Registered 8 July 2014.展开更多
Background Elevated intraocular pressure (lOP) is primarily due to increased aqueous outflow resistance, but how aqueous outflow resistance is generated and regulated are still not fully understood. The aim of this ...Background Elevated intraocular pressure (lOP) is primarily due to increased aqueous outflow resistance, but how aqueous outflow resistance is generated and regulated are still not fully understood. The aim of this study is to determine whether changes in outflow facility, outflow pattern, and morphology following acute lOP elevation were reversible when the lOP was returned to a normal level in bovine eyes using a two-color tracer technique to label outflow patterns within the same eye. Methods Twelve fresh enucleated bovine eyes were perfused with Dulbecco's phosphate buffer saline (PBS) containing 5.5 mmol/L glucose (DBG) at 30 mmHg first to establish the baseline outflow facility followed by a fixed volume of red fluorescent microspheres (0.5 μm, 0.002% v/v). After the red tracer being replaced with DBG in the anterior chamber, perfusion was continued at 7 mmHg with the same volume of green tracer, followed by a fixative. In two control groups, the eyes were constantly perfused at either 30 mmHg (n=6) or 7 mmHg (n=6) using the same methods. The outflow facility (C, pJ.min.-lmmHg-1), was continuously recorded. Confocal images were taken along the inner wall (IW) of the aqueous plexus (AP) in frontal sections. The percent of the effective filtration length (PEFL, PEFL=IW length exhibiting tracer labeling/total length of IW) was measured. Sections with AP were processed and examined by light microscopy. The total length of IW and the length exhibiting separation (SL) in the juxtacanalicular connective tissue (JCT) were measured. A minimum of eight collector channel (CC) ostia per eye were analyzed for herniations. Results In the experimental (30-7 mmHg) group, the outflow facility was significantly higher at 7 mmHg ((4.81±1.33) #lmin-1 mmHg-1) than that at 30 mmHg ((0.99±0.15) μl.min-1 mmHg-1, P=-0.002), corresponding to a significant increase in the PEFL (P=-0.0003). The percent of CC ostia exhibiting herniations in the experimental group ((67.40±8.90) μl.min·-1mmHg-1) decreased significantly compared to that in the control at 30 mmHg ((94.44±3.33) μl.min-lmmHg-1, P=-0.03), but higher than that in the control at 7 mmHg ((29.43±4.60) μl.min-1mmHg-1, P=0.01). Washout-associated separation between the IW and JCT was found by light microscopy and percent separation length (PSL, PSL=SL/total length of IW) was decreased in the control at 30 mmHg compared to that in the experimental group and control at 7 mmHg. Conclusions The pressure-induced morphological and hydrodynamic changes were reversible. Changes (collapse of AP, separation between the JCT and IW, and herniation into CC ostia) influence the effective filtration area that regulates outflow facility.展开更多
Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how centra...Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance my lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.31070840,10802053,and 81201123)the Natural Science Foundation of Beijing,China(Grant No.3122010)+2 种基金the Natural Science Foundation of Guangdong Province,China(Grant No.S2012040006576)the Shenzhen Science and Technology Innovation Committee,China(Grant No.KQCX20120816155352228)the Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality,China(Grant No.PHR201110506)
文摘As the aqueous humor leaves the eye, it first passes through the trabecular meshwork (TM). Increased flow resistance in this region causes elevation of intraocular pressure (IOP), which leads to the occurrence of glaucoma. To quantitatively evaluate the effect of high IOP on the configuration and hydraulic permeability of the TM, second harmonic generation (SHG) microscopy was used to image the microstructures of the TM and adjacent tissues in control (normal) and high IOP conditions. Enucleated rabbit eyes were perfused at a pressure of 60 mmHg to achieve the high lOP. Through the anterior chamber of the eye, in situ images were obtained from different depths beneath the surface of the TM. Porosity and specific surface area of the TM in control and high IOP conditions were then calculated to estimate the effect of the high pressure on the permeability of tissue in different depths. We further photographed the histological sections of the TM and compared the in situ images. The following results were obtained in the control condition, where the region of depth was less than 55 μm with crossed branching beams and large pores in the superficial TM. The deeper meshwork is a silk-like tissue with abundant fluorescence separating the small size of pores. The total thickness of pathway tissues composed of TM and juxtacanalicular (JCT) is more than 100 p.m. After putting a high pressure on the inner wall of the eye, the TM region progressively collapses and decreases to be less than 40 μm. Fibers of the TM became dense, and the porosity at 34 μm in the high IOP condition is comparable to that at 105 μm in the control condition. As a consequent result, the permeability of the superficial TM decreases rapidly from 120 μm2 to 49.6 μm2 and that of deeper TM decreases from 1.66 μm2 to 0.57 μm2. Heterogeneity reflected by descent in permeability reduces from 12.4 μm of the control condition to 3.74 μm of the high IOP condition. The persistently high IOP makes the TM region collapse from its normal state, in which the collagen fibers of the TM are arranged in regular to maintain the physiological permeability of the outflow pathway. In the scope of pathologically high IOP, the microstructure of the TM is sensitive to pressure and hydraulic permeability can be significantly affected by IOP.
基金Supported by the National Natural Science Foundation of China (No.81974133)。
文摘AIM:To observe the changes in Schlemm’s canal(SC),trabecular meshwork(TM),and anterior chamber relevant parameters after small incision lenticule extraction(SMILE) of myopia patients.METHODS:A total of 58 eyes from 30 patients who underwent SMILE were divided into a low and moderate myopia group(group A,32 eyes) and a high myopia group(group B,26 eyes).The diameter and area of the SC,the width and thickness of TM obtained by CIRRUS HD-OCT5000,and the related anterior chamber parameters obtained by Pentacam anterior segment analysis system,accommodation amplitude(AMP) were observed pre-and postoperatively.The preoperative intraocular pressure(IOP) and postoperative correction of intraocular pressure(IOPcc) were measured.RESULTS:The diameter and area of the SC in the two groups were significantly increased postoperatively(all P<0.01).The TM width of the patients in the two groups were increased at 1mo after surgery(both P<0.01),but the TM thickness did not change(P>0.05).The corneal curvature,central anterior chamber depth,and anterior chamber volume decreased after SMILE surgery(all P<0.01).There was a weak negative correlation between the SC area change and AMP change in group A(r=-0.362,P<0.01).The postoperative IOP decreased after correction by Shah formula(P<0.05).CONCLUSION:SC and TM in myopia patients change in the early postoperative stage of SMILE and the IOP is decline.
基金Supported by JSPS KAKENHI (No.15K10857No.17H00695No.19K18865)。
文摘AIM: To investigate changes in extracellular matrix(ECM) gene expression in human trabecular meshwork(HTM) cells in response to mechanical fluid flow stimulation.METHODS: HTM cells were grown on a glass plate coated with 0.02% type Ⅰ collagen(COL) and exposed to shear stress(0, 0.2, 1.0 dyne/cm;) for 12 h.Changes in genes related to the ECM were evaluated by real-time reverse transcriptase-polymerase chain reaction.Phosphorylation of Smad2 protein was investigated by Western blotting.RESULTS: After mechanical stimulation, COL type 4 alpha 2, COL type 6 alpha 1, and fibronectin-1 mRNA were significantly higher than the static control(P<0.05, <0.05, and <0.01, respectively).The metalloproteinase-2 and plasminogen activator inhibitor-1 mRNA were significantly higher than the static control(P<0.05 and <0.01, respectively), while the differences in the tissue inhibitors of metalloproteinases-2 mRNA were not significant.The phosphorylation of Smad2 levels was significantly higher compared to the static control cells.CONCLUSION: Changes in the expressions of genes associated ECM metabolism result in HTM cells after mechanical stimulation.The mechanical stimulation of the aqueous humor to the trabecular meshwork may promote ECM turnover and contribute to intraocular pressure homeostasis.
基金This work was supported by a grant from the General Projects of National Natural Science Foundation (No. 30471863).
文摘Background Trabecular meshwork (TM) cell volume may be an important determinant of aqueous humor outflow in the eye. This study aimed to evaluate the role of Hepll domain peptides V on corneal permeability, corneal endothelial cells, intraocular pressure (lOP) and morphology of trabecular meshwork in rats. Methods The lOP of rat eyes was measured before and 3, 5, 7 and 8 hours after topical delivery of Hepll domain peptides V through intracameral injections. The peptide's concentration in aqueous humor was assessed by high performance liquid chromatography (HPLC). The shape and density of endothelial cells were observed by laser confocal microscopy 8 hours, 3 and 14 days after intracameral injections of Hepll domain peptides V. The morphological changes in TM of rat eyes were assessed by transmission electron microscopy (TEM). Results Intracameral injection of Hepll domain peptides V significantly (P 〈0.001) decreased lOP by (5.71±2.10) mmHg in rats at 5 hours after injection. There were no obvious changes of the shape and the density of corneal endothelial cells. In addition, morphological changes in the TM of rats were observed including the expansion of intercellular spaces in the juxtacanalicular meshwork, removal of extracellular material, cellular relaxation, and cytoskeleton reorganization. Conclusions Hepll domain peptides V could not penetrate cornea and was safe to corneal endothelial cells. Hepll domain peptides V could significantly decrease lOP in rat probably by disorganizing actin cytoskeleton and cell-junction in the TM.
基金funded by research grants from the National Natural Science Foundation of China(Grant Nos.81870642,81970780,81470613,81100653,81670835,and 81270989)the National Key R&D Program of China(Grant No.2018YFC0116800)the Outstanding Youth Medical Talents Program of the Shanghai Health and Family Planning Commission(Grant No.2017YQ011).
文摘Purpose:To investigate the anterior segment in nanophthalmic eyes and their association with intraocular pressure after cataract surgery.Methods:Thirty-two nanophthalmic eyes(axial length[AL]<18.5 mm)in 18 patients and 35 normal eyes(21.0≤AL≤24.5 mm)in 35 controls who had undergone uneventful cataract surgery were included.Swept-source optical coherence tomography was used to compare the anterior segment structures between the two groups.The associations between the anterior segment characteristics of nanophthalmic eyes and postoperative intraocular pressure(IOP)were also investigated.Results:The IOP-lowering effect of cataract surgery was remarkably insufficient in nanophthalmic eyes.Peripheral anterior synechiae(PAS)were observed in 56%(18/32)of nanophthalmic eyes,and a characteristic boomerangshaped iris was observed in 28%(9/32).The anterior surface of the iris seemed"smoother"in nanophthalmic eyes than in normal eyes.Schlemm's canal(SC)diameter,SC area,trabecular meshwork(TM)thickness,TM width,and TM area were generally smaller in the nanophthalmic eyes.Younger age,higher preoperative IOP,broader PAS,and smaller SC area were main contributors to higher postoperative IOP.AL and SC diameter may also be of great importance in IOP prediction in patients without glaucoma surgery and PAS.Conclusions:The morphological features of the anterior segment in nanophthalmic eyes are significantly different from those of normal eyes.Influencing factors such as age,AL,preoperative IOP,extent of PAS,SC and TM size could all be prognostic for IOP after cataract surgery in nanophthalmic eyes.Trial registration:ClinicalTrails.gov,Trial registration number:NCT02182921,Registered 8 July 2014.
文摘Background Elevated intraocular pressure (lOP) is primarily due to increased aqueous outflow resistance, but how aqueous outflow resistance is generated and regulated are still not fully understood. The aim of this study is to determine whether changes in outflow facility, outflow pattern, and morphology following acute lOP elevation were reversible when the lOP was returned to a normal level in bovine eyes using a two-color tracer technique to label outflow patterns within the same eye. Methods Twelve fresh enucleated bovine eyes were perfused with Dulbecco's phosphate buffer saline (PBS) containing 5.5 mmol/L glucose (DBG) at 30 mmHg first to establish the baseline outflow facility followed by a fixed volume of red fluorescent microspheres (0.5 μm, 0.002% v/v). After the red tracer being replaced with DBG in the anterior chamber, perfusion was continued at 7 mmHg with the same volume of green tracer, followed by a fixative. In two control groups, the eyes were constantly perfused at either 30 mmHg (n=6) or 7 mmHg (n=6) using the same methods. The outflow facility (C, pJ.min.-lmmHg-1), was continuously recorded. Confocal images were taken along the inner wall (IW) of the aqueous plexus (AP) in frontal sections. The percent of the effective filtration length (PEFL, PEFL=IW length exhibiting tracer labeling/total length of IW) was measured. Sections with AP were processed and examined by light microscopy. The total length of IW and the length exhibiting separation (SL) in the juxtacanalicular connective tissue (JCT) were measured. A minimum of eight collector channel (CC) ostia per eye were analyzed for herniations. Results In the experimental (30-7 mmHg) group, the outflow facility was significantly higher at 7 mmHg ((4.81±1.33) #lmin-1 mmHg-1) than that at 30 mmHg ((0.99±0.15) μl.min-1 mmHg-1, P=-0.002), corresponding to a significant increase in the PEFL (P=-0.0003). The percent of CC ostia exhibiting herniations in the experimental group ((67.40±8.90) μl.min·-1mmHg-1) decreased significantly compared to that in the control at 30 mmHg ((94.44±3.33) μl.min-lmmHg-1, P=-0.03), but higher than that in the control at 7 mmHg ((29.43±4.60) μl.min-1mmHg-1, P=0.01). Washout-associated separation between the IW and JCT was found by light microscopy and percent separation length (PSL, PSL=SL/total length of IW) was decreased in the control at 30 mmHg compared to that in the experimental group and control at 7 mmHg. Conclusions The pressure-induced morphological and hydrodynamic changes were reversible. Changes (collapse of AP, separation between the JCT and IW, and herniation into CC ostia) influence the effective filtration area that regulates outflow facility.
基金supported by a grant from All India Institute of Medical Sciences,New Delhi (to RD and TD)Indian Council of Medical Research,Senior Research Fellowship Grant (3/1/2(24)/oph-2009-NCD-II,to MAF)+1 种基金Feldstein Medical Foundation Research Grant (to KCC)unrestricted fund from Research to Prevent Blindness to NYU Langone Health Department of Ophthalmology (to KCC)。
文摘Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance my lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.