Pericytes are smooth muscle-like cells with contractile properties, which provide structural integrity to the retinal microvasculature. Pericyte loss is considered as a hallmark of early diabetic retinopathy, which may cause blood-retinal barrier (BRB) breakdown leading to increased permeability of ...
Pericytes are smooth muscle-like cells with contractile properties, which provide structural integrity to the retinal microvasculature. Pericyte loss is considered as a hallmark of early diabetic retinopathy, which may cause blood-retinal barrier (BRB) breakdown leading to increased permeability of blood vessels and secretion of inflammatory cytokines. Several lines of evidence have implicated abnormal activation of protein kinase C (PKC) in this chain of events. Whereas no clinically approved PKC inhibitors are yet available, riluzole, a putative anti-glutamate drug currently used in amyotrophic lateral sclerosis (ALS), was shown to directly inhibit PKC. In the present study, we examined the possibility that riluzole attenuates the induction of cytokines in the retina of diabetic mice and in a human retinal pericyte cell line. In order to induce diabetes in mice, we intraperitoneally injected streptozotocin (STZ, 150 mg/kg). After 8 weeks of the onset of diabetes (blood glucose > 300 mg/dl), the permeability of retinal vessels was verified with fluorescein angiography performed with Micron III. In addition, fluorescein isothiocyanate staining of flat mounts revealed that the retinal vessels of diabetic mice were severely reduced in diameter, resulting in hypoperfusion. Immunostaining with an antibody to PDGFR-β, specific to pericyte, revealed that the number of pericytes was substantially reduced in retinas of diabetic mice. Since the induction of cytokines such as monocyte chemotactic protein (MCP-1) has been shown to play key roles in diabetic retinopathy, we then examined the level of MCP-1 in retinas of diabetic mice. In addition, we analyzed changes in MCP-1 levels in the human pericyte cell line following exposure to advanced glycation end product (AGE, 500 μg/ml), or modified low density lipoprotein (mLDL, 100 μg/ml), all of which have been implicated as causative factors for diabetic retinopathy. We confirmed that AGE and LDL all increased the levels of MCP-1, and that riluzole as well as GF109203X inhibited both changes in vivo and in vitro. Taken together, our results suggest that MCP-1 induction and pericyte loss are all attenuated in diabetic retinopathy by an anti-ALS drug riluzole, likely through its direct inhibitory effect on PKC.
Pericytes are smooth muscle-like cells with contractile properties, which provide structural integrity to the retinal microvasculature. Pericyte loss is considered as a hallmark of early diabetic retinopathy, which may cause blood-retinal barrier (BRB) breakdown leading to increased permeability of blood vessels and secretion of inflammatory cytokines. Several lines of evidence have implicated abnormal activation of protein kinase C (PKC) in this chain of events. Whereas no clinically approved PKC inhibitors are yet available, riluzole, a putative anti-glutamate drug currently used in amyotrophic lateral sclerosis (ALS), was shown to directly inhibit PKC. In the present study, we examined the possibility that riluzole attenuates the induction of cytokines in the retina of diabetic mice and in a human retinal pericyte cell line. In order to induce diabetes in mice, we intraperitoneally injected streptozotocin (STZ, 150 mg/kg). After 8 weeks of the onset of diabetes (blood glucose > 300 mg/dl), the permeability of retinal vessels was verified with fluorescein angiography performed with Micron III. In addition, fluorescein isothiocyanate staining of flat mounts revealed that the retinal vessels of diabetic mice were severely reduced in diameter, resulting in hypoperfusion. Immunostaining with an antibody to PDGFR-β, specific to pericyte, revealed that the number of pericytes was substantially reduced in retinas of diabetic mice. Since the induction of cytokines such as monocyte chemotactic protein (MCP-1) has been shown to play key roles in diabetic retinopathy, we then examined the level of MCP-1 in retinas of diabetic mice. In addition, we analyzed changes in MCP-1 levels in the human pericyte cell line following exposure to advanced glycation end product (AGE, 500 μg/ml), or modified low density lipoprotein (mLDL, 100 μg/ml), all of which have been implicated as causative factors for diabetic retinopathy. We confirmed that AGE and LDL all increased the levels of MCP-1, and that riluzole as well as GF109203X inhibited both changes in vivo and in vitro. Taken together, our results suggest that MCP-1 induction and pericyte loss are all attenuated in diabetic retinopathy by an anti-ALS drug riluzole, likely through its direct inhibitory effect on PKC.
주제어
#Diabetic retinopathy Pericyte cytokine Riluzole
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