| OBJECTIVE: Serum uric acid(SUA)is an independent risk factor for diabetic retinopathy(DR)in patients with type 2 diabetes mellitus(T2DM).After explored the quantitative relationship between SUA and DR,the animal and cell models of hyperuricemia(HUA)complicated with T2 DM were constructed to clarify the damage mechanism of UA to retina in a high-sugar environment.METHODS: The relationship between UA and DR was obtained through cross-sectional study,and the threshold of SUA to predict the risk of DR was obtained,then the conclusion was verified in a prospective study.Through OCT,fundus photography,fundus fluorescein angiography,electroretinogram,cell proliferation and migration experiments,the mechanism of retinal damage caused by UA in the high-sugar environment was explored.Results:(1)Of the 3700 T2 DM patients included in the cross-sectional study,213 patients(5.8%)had DR.There were significant differences among the NDR and DR groups in terms of duration of diabetes(9.4 ± 7.5 vs.14.2 ±7.7 years,p < 0.01),age of diagnosis(49 ± 11.7 vs.44 ± 10.1 years,p <0.01),SBP(131 ± 16.1 vs.138 ± 19.7 mm Hg,p < 0.01),DBP(79 ± 9.1vs.81 ± 10.5 mm Hg,p < 0.01),BMI(25.1 ± 4.0 vs.25.8 ± 3.3 kg/m2,p< 0.01),HDL(1.1 ± 0.3 vs.1.0 ± 0.3 mmol/L,p < 0.01),TG(1.7 [0.9-1.9]vs.2.1 [1.1-2.3] mmol/L,p < 0.01),CRP(4.4 [0.5-2.7] vs.3.0 [0.5-2.2]mmol/L,p < 0.01),SUA(301.1 ± 71.8 vs.370.1 ± 71.2 μmol/L,p < 0.01),chlorine(101.9 ± 3.4 vs.102.5 ± 3.4 mmol/L,p < 0.01),magnesium(0.88± 0.1 vs.0.85 ± 0.1 mmol/L,p < 0.01),and C peptide(4.6 ± 3.2 vs.3.4 ±2.2 mmol/L,p < 0.01).There were no differences in age,Hb A1 c,antidiabetic drugs,TC,LDL,Scr,and BUN between the two groups.After dividing patients into deciles by SUA values,the prevalence of DR in sixth SUA decile(304.0 μmol/L)was 3.235-fold(1.270-8.246,p =0.014)higher than that for patients in the first SUA decile(<213.0μmol/L),with odds ratios(OR)for DR increasing as SUA increased.In the prospective study,at 5-year follow-up,44 patients(26.2%)of 168 subjects with high SUA levels(304.0-404.0 μmol/L)developed DR,while 4 patients(2.0 %)of 198 subjects with lower SUA(<304.0 μmol/L)developed DR,and that there was a significant difference for prevalence of DR between the these two groups(26.2 % vs 2.0 %,P < 0.001).(2)The thickness of retina was detected after dilatation.The retinal thickness of T2DM+HUA group was significantly thinner than that of normal control group,T2 DM group and HUA group(p<0.05).The boundary layer of retinal layer was still clear,and the outer layer of photoreceptor was disappeared.There was no significant change in the retina between the T2 DM group and the HUA group compared with the normal control group.After fundus examination,the fundus examination of the eyes of the four groups of mice showed no changes in the fundus of diabetic retinopathy(DR)such as exudation,hemorrhage or proliferation.The retinal thickness of the T2DM+HUA group was significantly thinner than the normal control group,T2 DM group and HUA group(p<0.05),and the choroidal permeability was increased.The retina of T2 DM group and HUA group did not change significantly compared with the normal control group.Intraperitoneal injection of FFA(10%),the retinal vasculature filling time of the four groups of mice were normal,no obvious vascular occlusion or stenosis,and no obvious fluorescein leakage.(3)The ERG amplitudes of the four groups of mice increased with the increase of light intensity.The overall amplitude of ERG in the T2DM+HUA group was significantly lower than that of the normal control group,T2 DM group and HUA group(p<0.05).The b-wave decline in retinal photoreceptor function is most pronounced.The overall amplitude of ERG in the T2 DM group and the HUA group was lower than that in the normal control group,and the b wave was also decreased,but the difference between the groups was not significant.(4)P2 and P14 mice were stained with frozen sections of the retina,and EZH2 was expressed,mainly in the extraretinal segmental layer.The retina of P2 mouse has not yet fully developed,and the boundaries between layers are still unclear.P14 mice expressed less EZH2 than P2.(5)The expression of Ezh2、NF-κB、IL-1β in T2DM+HUA group was significantly higher than that in normal control group,T2 DM group and HUA group(p<0.05).The expression of Ezh2、NF-κB、IL-1β in T2 DM group and HUA group was higher than that in normal control group.However,the difference was not statistically significant,and there was no significant difference between the two groups.(6)The expressions of EZH2,NF-κB,NLRP3 and IL-1β in T2DM+HUA group were significantly higher than those in normal control group,T2 DM group and HUA group(p<0.05).The expression of EZH2,NF-κB NLRP3 and IL-1β in T2 DM group and HUA group was higher than that of the normal control group,but the difference was not statistically significant,and there was no significant difference between the two groups.(7)Under high glucose environment,the relative absorbance of HRMECs was negatively correlated with the concentration of MSU after the gradient concentration of MSU was applied to HRMEC.The cell proliferation was most inhibited under 200 μg/m L MSU.(8)Under high glucose environment,200 μg/m L MSU was added to HRMECs.After 48 h,the number of cells migrated to the scratched area increased more than 0h after dosing.HRMECs in the HG+HUA group migrated to the blank area most.(9)After cultured HRMECs with high glucose and 200 μg/m L MSU for 48 h,the microfilament structure of HG+HUA group was denser than that of normal control group,HG group and HUA group,and the clusters were denser at the proximal edge of the cell.Sharper.It is suggested that the enhancement of cell migration motility is related to microfilament changes.Conclusion: SUA threshold(304.0 μmol/L)can be used to predict the risk of DR in patients with T2 DM.UA can promote the expression of methyltransferase EZH2 in retina and activate the NF-κB inflammatory signaling pathway in the high-sugar environment,leading to the thinning of the outer retinal segment and the destruction of the BRB barrier,aggravating the retinal damage. |
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