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KATP Opener Attenuates Diabetic-Induced Müller Gliosis and Inflammation by Modulating Kir6.1 in Microglia
Hong Li1,2, Donglong Chen2, Wei Sun3
1AIER School of Ophthalmology, Central South University, Changsha, China.
Purpose:
This study aimed to determine the effect of pinacidil, a nonselective KATP channel opener, on diabetes-induced retinal gliosis and inflammation.
Methods:
Primary and immortalized cell lines of retinal microglia and Müller cells were used to set up a coculture model. In the trans-well system, microglia were seeded in the upper chamber and Müller cells in the bottom chamber. Microglia were polarized into proinflammatory (M1, with lipopolysaccharide and INF-γ) with or without different pinacidil concentrations before coculturing with Müller cells. The expression of inflammatory or anti-inflammatory genes and protein in microglia, and the expression of glial fibrillary acidic protein (GFAP), Kir4.1, and AQP4 in Müller cells were examined by real-time polymerase chain reaction and Western blot. Pinacidil was injected intravitreally into streptozotocin-induced diabetic rats. Retinal gliosis and inflammation were examined by immunohistochemistry and Western blot.
Results:
Intravitreal injection of pinacidil alleviated diabetes-induced Müller cell gliosis and microglial activation and reduced vascular endothelial growth factor expression. In vitro study demonstrated that pinacidil inhibited tumor necrosis factor and interleukin-1β expression in M1-type microglia and alleviated the M1 microglia-induced GFAP expression in the Müller cells. Furthermore, we found that pinacidil on its own, or in combination with IL-4, can upregulate arginase-1 (Arg-1) and Kir6.1 expression in microglial cells.
Conclusions:
Our results suggest that potassium channels are critically involved in diabetes-induced gliosis and microglial activation. The KATP opener, pinacidil, can reduce microglial activation by upregulating Kir6.1 expression.
Insights
Pinacidil, a KATP channel opener, reduces diabetes-induced retinal gliosis and microglial activation. It works by upregulating Kir6.1 expression, suggesting potassium channels are key in this process.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Diabetic retinopathy is a leading cause of vision loss.
- Diabetes induces retinal gliosis and inflammation, involving Müller cells and microglia.
- KATP channels play a role in cellular responses to metabolic stress.
Purpose of the Study:
- To investigate the effect of pinacidil, a KATP channel opener, on diabetes-induced retinal gliosis and inflammation.
- To elucidate the mechanisms by which pinacidil modulates microglial activation and Müller cell responses.
Main Methods:
- A coculture model of retinal microglia and Müller cells was established.
- Microglia were polarized to a pro-inflammatory M1 phenotype with or without pinacidil.
- Pinacidil was administered intravitreally in streptozotocin-induced diabetic rats.
- Gene and protein expression (GFAP, Kir4.1, AQP4, inflammatory markers, Arg-1, Kir6.1) were analyzed using RT-PCR and Western blot.
- Retinal gliosis and inflammation were assessed via immunohistochemistry and Western blot.
Main Results:
- Intravitreal pinacidil alleviated diabetes-induced Müller cell gliosis and microglial activation.
- Pinacidil reduced vascular endothelial growth factor expression in diabetic rat retinas.
- In vitro, pinacidil inhibited pro-inflammatory cytokine (TNF-α, IL-1β) expression in M1 microglia.
- Pinacidil mitigated M1 microglia-induced GFAP expression in Müller cells.
- Pinacidil upregulated arginase-1 (Arg-1) and Kir6.1 expression in microglial cells.
Conclusions:
- Potassium channels are critically involved in diabetes-induced retinal gliosis and microglial activation.
- The KATP channel opener pinacidil effectively reduces microglial activation.
- Upregulation of Kir6.1 expression by pinacidil is a key mechanism in mitigating microglial activation.
