Inhibition of HIF-1α decreases expression of pro-inflammatory IL-6 and TNF-α in diabetic retinopathy.
OBJECTIVE
Recent studies demonstrate that pro-inflammatory cytokines (PICs, i.e. IL-1β, IL-6 and TNF-α) in retinal tissues are likely involved in the development of diabetic retinopathy (DR). In this report, we particularly examined contributions of hypoxia inducible factor subtype 1α (HIF-1α) to the expression of PICs and their receptors in diabetic retina.


METHODS
Streptozotocin (STZ) was systemically injected to induce hyperglycaemia in rats. ELISA and Western blot analysis were employed to determine the levels of HIF-1α and PICs as well as PIC receptors in retinal tissues of control rats and STZ rats.


RESULTS
The levels of retinal HIF-1α were significantly increased in STZ rats 4-10 weeks after induction of hyperglycaemia as compared with control animals. With increasing HIF-1α retinal PICs including IL-1β, IL-6 and TNF-α, their respective receptors, namely IL-1R, IL-6R and TNFR1, were also elevated in STZ rats. Moreover, inhibition of HIF-1α by injection of 2-methoxyestradiol (2-MET) significantly decreased the amplified expression IL-6, TNF-α, IL-6R and TNFR1 in diabetic retina, but did not modify IL-1β pathway. In addition, we examined protein expression of Caspase-3 indicating cell apoptosis in the retina of STZ rats after infusing 2-MET, demonstrating that 2-MET attenuated an increase in Caspase-3 evoked by STZ.


CONCLUSIONS
Hypoxia inducible factor subtype 1α (HIF-1α) activated in diabetic retina is likely to play a role in regulating pathophysiological process via IL-6 and TNF-α mechanism. This has pharmacological implications to target specific HIF-1α, IL-6 and TNF-α signalling pathway for dysfunction and vulnerability related to DR.
Department of Ophthalmology, Jining Medical University Affiliated Hospital, Jining City, Shandong Province, China.
Xiuhua
X
Gao
Department of Ophthalmology, Jining Medical University Affiliated Hospital, Jining City, Shandong Province, China.
Yonghua
Y
Li
Department of Ophthalmology, Jining Medical University Affiliated Hospital, Jining City, Shandong Province, China.
Hongxia
H
Wang
Department of Ophthalmology, Jining Medical University Affiliated Hospital, Jining City, Shandong Province, China.
Chuanbao
C
Li
Department of Ophthalmology, Jining Medical University Affiliated Hospital, Jining City, Shandong Province, China.
Jianguang
J
Ding
D000077584:2-Methoxyestradiol; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism*; D050257:Tubulin Modulators / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D050257:Tubulin Modulators; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D000077584:2-Methoxyestradiol
Caspase-3; Cytokines; Diabetic retinopathy; HIF-1α