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Upregulation of retinal neuronal MCP-1 in the rodent model of diabetic retinopathy and its function in vitro.

PURPOSE
To evaluate the expression of monocyte chemoattractant protein-1 (MCP-1) in the rodent model of diabetic retinopathy (DR) and to study the stimulation of microglial activation by retinal neuronal MCP-1 in vitro.


METHODS
Diabetes mellitus was induced by streptozotocin (STZ) injection. The expression of MCP-1 was determined using immunohistochemical methods, Western blotting and RT-PCR analyses. Retinal neurons and microglia were separated and co-cultured in a Transwell apparatus. The levels of soluble MCP-1 that were produced after stimulation of retinal neurons by adding advanced glycation end products (AGEs) to the medium were measured by ELISA. The degree of microglial activation was measured by testing microglial migration and the level of soluble TNF-α in the medium by ELISA. The ability of neuronal MCP-1 to stimulate microglia activation was examined by pre-exposing the retinal neurons to AGEs and an MCP-1 antibody or to AGEs and SiRNA specific to MCP-1.


RESULTS
A marked increase in the expression of MCP-1 was detected 4 weeks after STZ injection, and the expression was consistently upregulated at 3 and 5 months in the rodent DR model. Stimulation with AGEs significantly increased the expression of MCP-1 in retinal neurons, which activated microglial cells, including increased microglial migration and upregulated secretion of TNF-α. Retinal neurons that were pre-exposed to AGEs and an MCP-1 antibody or MCP-1 knockdown displayed greatly reduced microglial migration and TNF-α secretion.


CONCLUSIONS
Upregulation of MCP-1 began during the early stage of DR and increased with the development of the disease. Retinal neurons are the main source of MCP-1, and they play an important role in retinal microglial activation, which may be an important link in the pathogenesis of DM.