High Mobility Group Box-1: A Missing Link between Diabetes and Its Complications

Table 3

HMGB-1 in DR (diabetic retinopathy).

Pathological phenomenon(s)	Related signal molecule(s)	Notes	Ref.
Angiogenesis	HMGB-1, VEGF, sVE-cadherin, sEng	HMGB-1, VEGF, sVE-cadherin, and sEng levels were higher in PDR patients than in nondiabetics.; HMGB-1 was positively correlated with sVE-cadherin.	[53]
Angiogenesis	HMGB-1, RAGE, VEGF, CXCL12/CXCR4, HIF-1α, early growth response-1, tyrosine kinase-2	HMGB-1 induced upregulation of CXCL12/CXCR4, HIF-1α, early growth response-1, and tyrosine kinase-2 in diabetic retinas.; HMGB-1 induced VEGF and VEGFR2 expression in HRMEC.	[54]
Angiogenesis and fibrosis	HMGB-1, OPN, CTGF	Upregulated HMGB-1 level in PDR and PVR patients compared with quiescent RD patients.	[55]
Neovascularization	HMGB-1, VEGF-A	HMGB-1 mediated AGE-induced VEGF-A production in RGC-5 cells.	[56]
Inflammation, neovascularization, and hemorrhage	HMGB-1, MCP-1, sICAM-1	HMGB-1 was related to neovascularization and hemorrhage in PDR patients.; HMGB-1 expression was upregulated in the retinas of diabetic mice.	[57]
Inflammation and disrupted retinal vascular barrier	HMGB-1, RAGE, ERK, NF-κB, ICAM-1	Increased expression of HMGB-1, RAGE, ERK, and NF-κB in diabetic retinas.; HMGB-1 reduced transendothelial electrical resistance of bovine retinal endothelial cells.; HMGB-1 induced upregulation of ICAM-1, sICAM-1, HMGB-1, RAGE, ERK, and NF-κB and increased retinal vascular permeability.	[58]
Inflammation	HMGB-1, RAGE, NF-κB	Cytoplasmic translocation of HMGB-1 in diabetes and high glucose in retinal pericytes.	[59]
Inflammation	HMGB-1, NF-κB, TNF-α, VEGF	HMGB-1, receptors for HMGB-1, NF-κB, TNF-α, and VEGF were upregulated in diabetic retinas and HG-induced ARPE-19 cells.; HMGB-1 blockage alleviated HG-induced expression of NF-κB and VEGF in ARPE-19 cells.	[29]
Apoptosis	HMGB-1, TLR4, NF-κB	Inhibition of HMGB-1 decreased expressions of TLR4 and NF-κB in high-glucose-induced RGC-5 cells.	[60]
Apoptosis	HMGB-1, NADPH oxidase, IL-1beta, Nox2, PARP-1, caspase-3	HMGB-1 and oxidative stress levels in vitreous fluid from PDR patients were higher than in controls.; HMGB-1 was positively associated with oxidative stress level.; HMGB-1 induced IL-1beta, ROS, Nox2, PARP-1, and cleaved caspase-3 expressions in HRMEC and in the retinas of rats.	[61]
Apoptosis	HMGB-1, RAGE	HMGB-1/RAGE expressions as well as apoptosis cells in diabetic rat retina were higher than in controls.	[62]
Neurodegeneration	HMGB-1, BDNF, TBARS, caspase-3, sRAGE, sICAM-1	Decreased serum BDNF and increased serum HMGB-1, sRAGE, sICAM-1, and TBARS in PDR patients.; HMGB-1 was negatively correlated with BDNF.; HMGB-1 induced upregulation of TBARS and cleaved caspase-3 and downregulated expression of BDNF and synaptophysin in rat retinas.	[63]

VEGF: vascular endothelial growth factor; sVE-cadherin: soluble vascular endothelial-cadherin; sEng: soluble endoglin; PVR: proliferative vitreoretinopathy; OPN: osteopontin; CTGF: connective tissue growth factor; RD: rhegmatogenous retinal detachment with no PVR; MCP-1: chemoattractant protein-1; sICAM-1: soluble intercellular adhesion molecule-1; BDNF: brain-derived neurotrophic factor; TBARS: thiobarbituric acid reactive substances; sRAGE: soluble receptor for advanced glycation end products; HRMEC: human retinal microvascular endothelial cell; IL-1beta: interleukin-1beta; Nox2: NADPH oxidase-2; PARP-1: poly(ADP-ribose) polymerase-1; NF-κB: nuclear factor-κB; ERK: extracellular signal-regulated kinase; HIF-α: hypoxia-inducible factor-1α; VEGFR2: vascular endothelial growth factor receptor-2; AGE: advanced glycation end product; RGC-5: retinal ganglion cell line 5; Ref.: references.