The Unfolded Protein Response and Diabetic Retinopathy

Table 1

Implications of UPR pathways in retinal pathophysiology pertinent to DR.

Branch of UPR	Cell type	Function	Involved mechanism(s)	References
IRE1/XBP1	MRPE cells, ARPE-19 cells	Apoptosis	Oxidative stress and Bcl-2 signaling	[21, 122]
IRE1/XBP1	HRECs	Hypoxia- or TNF-α-induced inflammation	TNF-α/IKK/IκB/NF-κB, and VEGF	[12, 51]
IRE1/XBP1	BRECs	VEGF- or high glucose-induced angiogenesis	VEGF degradation	[59]
IRE1/XBP1	ARPE19 cells	Proliferation	Not mentioned	[123]
IRE1/XBP1	ARPE19 cells	Inflammation and angiogenesis	VEGF transcriptional regulation	[124]
IRE1/XBP1	rMC-1	Inflammation and apoptosis	Oxidative stress, inflammasome, and autophagy	[74]
IRE1/XBP1	RGCs	Ischemia-, NMDA-, or IOP-induced apoptosis	Rat model, ASK1, SEK1, and pJNK	[68, 70]
ATF6	BRECs	Angiogenesis	VEGF degradation	[59]
ATF6	MIO-M1	Apoptosis	Oxidative stress	[73]
PERK/ATF4/CHOP	HRECs, TR-iBRB	Inflammation	TNF-α, ICAM-1, VEGF, STAT3 signaling	[12, 18]
PERK/ATF4/CHOP	rMC-1	High glucose-induced inflammation	JNK signaling, HIF-1α/VEGF	[15]
PERK/ATF4/CHOP	HRP	High glucose-induced inflammation	MCP-1 and VEGF	[53]
PERK/ATF4/CHOP	ARPE-19 cells	Apoptosis	Oxidative stress and mitochondrial dysfunction mediate apoptosis	[122]
PERK/ATF4	ARPE-19 cells	Inflammation and apoptosis	VEGF transcriptional regulation and oxidative stress	[65, 122, 125]
PERK/ATF4/CHOP	HRP	Apoptosis	Oxidative stress, mitochondrial dysfunction, and autophagy	[16, 52]
PERK/CHOP	hTERT-RPE	High glucose-induced apoptosis	Oxidative stress, mitochondrial dysfunction, and autophagy	[17]
PERK/CHOP	MIO-M1	Apoptosis	Oxidative stress	[73]
PERK/CHOP	RGCs, RGC-5	NMDA-, IOP-, or diabetes/high glucose-induced apoptosis	Neurotrophin-4	[69–71, 126]

HRECs: human retinal endothelial cells; HUVECs: human umbilical vein endothelial cells; HARCs: human aortic endothelial cells; BRECs: bovine retinal endothelial cells; TR-iBRB: immortalized rat retinal capillary endothelial cells; rMC-1: rat retinal Müller cells; HRP: primary human retinal pericytes; MIO-M1: human retinal Müller cells; RGCs: retinal ganglion cells; RGC-5: a rat ganglion cell line transformed with E1A virus; MRPE cells: primary mouse RPE cells; ARPE-19: an immortalized human RPE cell line; hTERT-RPE: RPE cells immortalized with hTERT.