Abstract
Purpose :
Retinal vein occlusion (RVO) is the second most common retinal vascular disease. Blockade of retinal veins initiated an inflammtory response and activated the resident retinal glias, which may further excerbated blood-retinal breakdown and caused irreversible loss of retinal neurons. Pyroptosis is a newly described form of inflammatory programmed cell death that is solely regulated by Gasdermin D, an inflammasome-activated membrane “pore-forming” protein. Canagliflozin, as one of a sodium-glucose cotransporters 2 inhibitors (SGLT-2i), has shown pleiotropic effects against ischemia/reperfusion brain damage. Thus, in the present study, we tested Canagliflozin’s anti-inflammatory and neuroprotective potential against RVO and investigated the underlying mechanisms.
Methods :
A mouse model of laser-induced RVO were introduced to C57BL/6J mice.Mice were fed with regular or Canagliflozin-containing chow. Retinal visual dysfunction and vascular dropout was assessed by electroretinogram (ERG) and fundus fluorescein angiography (FFA). Retinal flatmount was utilized to detect activation of microglia cells (MGs) and attenuation of retinal ganglion cells (RGC). The death of RGCs was evaluated with TUNEL staining on retinal cryosections. Retinal distribution and expression the major executors of pyroptosis were determined by immnunostaining or western-blotting analysis.
Results :
The retinal a-wave and b-wave amplitude were dramatically reduced and capillary nonperfusion were extensively formed in the lasered mice, which was significantly ameliorated by Canagliflozin.Canagliflozin markedly inhibited laser-induced retinal activation of MGs and massive loss of RGCs.Interestingly, a novel amino-terminal p40 fragment of Gasdermin D were found in retinas of RVO mice, which were mainly expressed by MGs.Furthermore, Canagliflozin intervention significantly reduced the release of IL-1β and IL-18 mediated by p40 gasdermin D and then markedly ameliorated pyroptosis of RGCs.
Conclusions :
Taken together, a novel amino-terminal p40 fragment Gasdermin D may mediate glia-neuron crosstalk and be responsible for loss of RGCs in retinas of RVO mice. Canagliflozin protected the retinal neuron damage, at least, partially via attenuating p40 Gasdermin D executed pyroptosis
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.