Targeting TRP channels for the restoration of microvascular barrier function in diabetic macular oedema

Background/Aims: Diabetic macular oedema (DMO) is characterised by retinal microvascular leakage, resulting in vision loss. Recent studies have suggested that endothelial TRP channels play an important role in the regulation of vascular permeability and numerous TRP channel activating molecules are known to be upregulated in the diabetic eye. The aim of this study is to investigate whether aberrant activation of retinal endothelial TRP channels may contribute to the development of DMO.

Methods: High-throughput Ca2+ assays were performed to determine which factors upregulated in the diabetic eye mobilise [Ca2+]i in human retinal microvascular endothelial cells (HRMECs). RNA-sequencing data was analysed to evaluate TRP channel expression profiles in HRMECs. The involvement of specific TRP channels in [Ca2+]i responses was determined using selective TRP channel antagonists.

Results: A panel of seventeen TRP channel activators known to be upregulated in the diabetic eye were tested for their ability to elevate [Ca2+]i in HRMECs. Of these, histamine, thrombin, lysophosphatidylcholine (LPC) and 4-oxo-nonenal (4-ONE) elicited large [Ca2+]i responses with EC50 values in the nanomolar or low micromolar range. HRMECs were found to express a range of TRP channels, including TRPC1,4 and 5, TRPV1,2 and 4, and TRPM7. HRMEC [Ca2+]i responses to histamine, thrombin, LPC and 4-ONE were inhibited to varying degrees by antagonists of TRPV1, 2, 4 and TRPM7 channels.

Conclusions: Multiple retinal endothelial TRP channels are activated by factors elevated in the diabetic eye. The involvement of these channels in mediating retinal vasopermeability responses during diabetes is currently being investigated.