The Effects Of Uric Acid On Endothelial Dysfunction In Early Chronic Kidney Disease And Its Mechanisms

BackgroundCardiovascular disease (CVD) is the most common complication and the major cause of death in patients with chronic kidney disease (CKD). Recent studies have found that even in early CKD patients, the risk of CVD increased obviously, not only in those with end stage renal disease. But the mechanisms of cardiovascular disease in early CKD is still uncertain. Our earlier clinical study found that serum uric acid increased in patients with stage 2-3 CKD, and was related with CVD, such as left ventricular hypertrophy and so on, indicating that hyperuricemia has some associations with CVD in early CKD. Endothelial dysfunction such as decreased NO level, increased ET-1 level, and decreased NO/ET-1 ratio, is the early performance of CVD, and is an important predicate factor for atherosclerosis, related with hypertension, coronary heart disease, thrombosis, and so on. Is there any relation between uric acid and endothelial dysfunction in early CKD?What is the realation?What are the mechanisms? This research is going to study the relation between uric acid and endothelial dysfunction , as well as its mechanisms.Objective: By establishing the early CKD animal model with hyperuricemia, we studied the relation between uric acid and endothelial dysfunction in early CKD and its mechanisms.Methods: The animal model was established by right-side nephrectomy and feeding with potassium oxonate,an inhibitor of uric acid enzyme (with a dose of 800mg/Kg, twice daily ) , for 10 weeks. We measured the indices including serum creatinine (Scr), serum uric acid (UA), serum nitric oxide(NO), serum endothelin-1(ET-1), serum C-reactive protein (CRP), serum malonaldehyde (MDA), serum super oxide dismutase (SOD) , serum oxidatively modified low density lipoprotein (ox-LDL) , serum low density lipoprotein(LDL) , the pathology of kidney and artery , collagen I of artery in the experimental group, then compared these indices with those in other two groups. Furthermore, the relation between uric acid and endothelial dysfunction indices in early CKD as well as its mechanisms were analysed.Results:(1)In our study, there was no obvious pathological change in the kidney of the sham-operation group. The main pathological change in the experimental group was mild glomerular mesangial proliferation but no obvious pathological change in the renal tubule and the renal interstitium . Compared with the right-side nephrectomy group and the sham-operation group, the experimental one had significant higher level of UA, but there was no obvious difference in Scr among the three groups.(2)There was no obvious pathological change in the artery of the sham-operation group. However, in the experimental one, the endothelial cells partly dropped from the artery, and the gap between them broadened. The smooth muscle cells proliferated in the experimental group, and there was obvious more collagen I deposited in the artery. The pathological change of the right-side nephrectomy group was similar to the experimental group, but more minor. The experimental group had higher level of the percentage of collagen I positive area (group a 12. 90±2. 31 %, group b 12.97±2.71%, group c 22.38±3.14%, group c vs group c ap<0. 01, group c vs group c b p<0. 01) .The experimental group had lower level of serum nitric oxide (μmol/L) (group a 47. 55±5. 39, group b 45. 34±4. 76, group c 36. 71±3. 45, group c vs group a p<0. 01, group c vs group b p<0. 01) , higher level of serum endothelin-1(pg/ml) (group a 5.89±1.67, group b 5.92±1.56, group c 7.50±1.06, group c vs group a p<0.05, group c vs group b p<0. 05) ,and lower level of NO/ET-1 ratio (group a 8. 18+2.32, group b 8.90±3.55, group c 5.07±1. 19, group c vs group a p<0.01, group c vs group b p<0. 01) .(3)Linear regression analysis showed that the level of serum uric acid had significant positive correlations with serum ET-1 (r=0. 9374, p<0. 01) and the percentage of collagen I positive area (r=0. 8403, p<0. 01) , but negative correlations with serum NO (r = -0. 9462, p<0. 01)and NO/ET-1 ratio (r=-0. 9230, p<(0. 01). The percentage of collagen I positive area had significant positive correlation with serum ET-1 (r = 0.8737, p<0. 01) , but negative correlations with serum NO (r=-0. 9171, p<0. 01) and NO/ET-1 ratio (r=-0. 8707, p<0. 01) .(4)The experimental group had lower level of serum super oxide dismutase (U/ml) (group a 249. 80±9. 83, group b 243. 60±8. 11, group c 224. 40±6. 47, group c vs group a p<0. 01, group c vs group b p<0. 01) , and higher level of serum malonaldehyde(nmol/ml)( group a 4. 06±0. 28, group b 4. 04±0. 41, group c 4. 40±0. 23, group c vs group a p<0. 01, group c vs group b p<0. 05) , higher level of serum C-reactive protein(ug/ml) (group a 10.43±1.68, group b 12. 27±2. 76, group c 14.68±2.01, group c vs group a p<0. 01, group c vs group b p<0. 05) , higher level of serum low density lipoprotein (mol/L) (group a 0. 18±0. 06, group b 0.18±0.06, group c 0.25±0.06, group c vs group a p<0. 01, group c vs group b p<0. 05) and higher level of serum oxidatively modified low density lipoprotein (mmol/L) (group a 47. 50±11. 51, group b 53.31±12.38, group c 65.22±10.91, group c vs group a p<0. 01, group c vs group b p<0. 05) .The level of serum uric acid had significant positive correlations with serum MDA(r=0. 8195, p<0. 01), serum CRP(r=0. 7251, p<0. 05), serum ox-LDL(r=0. 8479, p<0. 01) and serum LDL(r=0. 6356, p<0. 05), but negative correlation with serum SOD (r=-0. 6885, p<0.05).The percentage of collagen I positive area had significant positive correlations with serum MDA(r=0. 8015, p<0. 07) and serum CRP(r=0. 6752, p<0. 05), but negative correlation with serum SOD(r=-0. 8180, p<0. 01), and no significant correlations with serum ox-LDL(r=0. 5266, p>0. 05)or serum LDL(r=0. 5902, p>0. 05). Multiple stepwise regression analysis showed that serum SOD entered the equation, and the equation was y=1 11. 437-0. 397x₁ (y = the percentage of collagen I positive area, x₁ = SOD, 111.437 was constant) .The level of serum NO had significant positive correlation with serum SOD(r=0. 8179, p<0. 01), but negative correlations with serum MDA(r =-0.9171, p<0.01), serum CRP(r=-0. 7554, p<0. 05) and serum ox-LDL(r =-0.7459, p<0. 05), and no significant correlation with serum LDL(r =-0.5080, p>0. 05). Multiple stepwise regression analysis showed that serum SOD and CRP entered the equation, and the equation was y=0. 315x₁-0. 802x₂-22. 120 (y=N0, x₁=SOD, x₂=CRP, -22. 120 was constant).The level of serum ET-1 had significant positive correlations with serum MDA(r=0.8658, p<0.01), serum CRP(r=0. 7447, p<0. 05) and serum ox-LDL(r=0.7900, p<0. 01), but negative correlation with serum S0D(r = -0.7793, p<0.01), and no significant correlation with serum LDL(r =0.5734, p>0.05). Multiple stepwise regression analysis showed that serum SOD and ox - LDL entered the equation, and the equation was y=0.051x₁-0.082x₂ + 22.517 (y = ET-1, x₁ = ox-LDL, x₂ = S0D, 22.517 was constant).NO/ET-1 ratio had significant positive correlation with serum SOD(r =0. 8143, p<0. 01), but negative correlations with serum MDA(r=-0. 9143, p<0.01), serum CRP(r=-0. 8042, p<0. 01) and serum ox-LDL(r=-0. 7949, p<0.01), and no significant correlation with serum LDL(r=-0. 4947, p>0. 05). Multiple stepwise regression analysis showed that serum SOD and CRP entered the equation, and the equation was y=0. 102x₁-0. 316x₂-13. 151 (y=NO/ET-l ratio, x₁=SOD, x₂=CRP, -13. 151 was constant).Conclusions: By right-side nephrectomy and feeding the rats with potassium oxonate for 10 weeks, we successfully established the model of early chronic kidney disease with hyperuricemia. We found that endothelial dysfunction in the experimental group was significante, and the degree has significant positive correlation with the level of serum uric acid. Endothelial dysfunction in early CKD with hyperuricemia perhaps related with oxidative stress, micro-inflammation, lipidoxidative.