Tissue inhibitor of metalloproteinase-3 ameliorates diabetes-induced retinal inflammation
Purpose
Endogenous tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) has powerful regulatory effects on inflammation and angiogenesis. We investigated the role of TIMP-3 in regulating inflammation in the diabetic retina.
Methods
Vitreous samples from patients with proliferative diabetic retinopathy (PDR) and non-diabetic patients were subjected to Western blot analysis. Streptozotocin-treated rats were used as a preclinical diabetic retinopathy (DR) model. Blood-retinal barrier (BRB) breakdown was assessed with fluorescein isothiocyanate-conjugated dextran. Rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied.
Results
Intravitreal injection of TIMP-3 attenuated diabetes-induced BRB breakdown. This effect was associated with downregulation of diabetes-induced upregulation of the p65 subunit of NF-KB, intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF). In Müller cell cultures, TIMP-3 significantly attenuated VEGF upregulation induced by high-glucose (HG), the hypoxia mimetic agent cobalt chloride (CoCl2) and TNF-Alpha and attenuated MCP-1 upregulation induced by CoCl2 and TNF-Alpha. TIMP-3 attenuated HG-induced upregulation of phospho-ERK1/2, caspase-3 and the mature form of ADAM17 in Müller cells. TIMP-3 significantly downregulated TNF-Alpha-induced upregulation of ICAM-1 and VCAM-1 in HRMECs. TIMP-3 significantly decreased spontaneous and TNF-Alpha-and VEGF-induced adherence of monocytes to HRMECs. TIMP-3 significantly attenuated VEGF-induced migration, chemotaxis and proliferation of HRMECs.
Conclusion
In vitro and in vivo data point to the anti-inflammatory and anti-angiogenic effects of TIMP-3.
Conflict of interest
No
Authors 1
Last name
ABU EL-ASRAR
Initials of first name(s)
A
City
Riyadh
Country
Saudi Arabia
Authors 2
Last name
AHMAD
Initials of first name(s)
A
City
Riyadh
Country
Saudi Arabia
Authors 3
Last name
NAWAZ
Initials of first name(s)
M
City
Riyadh
Country
Saudi Arabia
Authors 4
Last name
SIDDIQUEI
Initials of first name(s)
M
City
Riyadh
Country
Saudi Arabia
Authors 5
Last name
ZUTTER
Initials of first name(s)
A
City
Riyadh
Country
Saudi Arabia
Authors 6
Last name
VAN BRABANT
Initials of first name(s)
L
City
Leuven
Country
Belgium
Authors 7
Last name
GIKANDI
Initials of first name(s)
P
City
Riyadh
Country
Saudi Arabia
Authors 8
Last name
STRUYF
Initials of first name(s)
S
City
Leuven
Country
Belgium
Authors 9
Last name
OPDENAKKER
Initials of first name(s)
G
City
Leuven
Country
Belgium
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