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目的观察氯沙坦对伴血尿酸(SUA)升高的早期慢性肾脏病(CKD)大鼠心脏病变影响并探讨可能机制。方法实验大鼠随机分成A组(假手术组)、B组(CKD组)、C组(伴SUA升高的CKD组:CKD+氧嗪酸钾(OXO))、D组(伴SUA升高的CKD+氯沙坦组:CKD+OXO+氯沙坦),每组15只。采用右肾切除+OXO连续灌胃法制备SD雄性大鼠伴SUA升高早期CKD模型;OXO剂量为800mg·kg-1·次-1,每天2次。D组氯沙坦剂量:20mg·kg-1·次-1,每天1次。16周后处死大鼠,检测血清肌酐(Scr)、SUA、氧化型低密度脂蛋白(ox-LDL)、超氧化物歧化酶(SOD);HE和PAS染色观察肾组织病理改变;HE染色观察心脏病理改变,免疫组化法测定心肌I型胶原(Col I)表达情况。结果 (1)4组Scr水平无显著差异,C组SUA较其余3组明显升高。与A组相比,其余3组肾组织HE、PAS染色仅有轻微肾小球系膜增生。(2)A组心脏HE染色未见明显形态学改变,心肌Col I少量沉积。B组心肌细胞间存在少量散在炎症细胞,Col I沉积少量增加。C组大量炎症细胞浸润,间质充血、纤维化;小血管壁可见成纤维细胞出现;Col I沉积显著增多。D组病变与C组相似,但程度显著减轻,仅有少量炎症细胞浸润,血管壁偶见炎症细胞,Col I沉积显著减少。统计学分析显示:C组心肌Col I阳性面积百分比较B组显著升高,D组则较C组显著降低。单因素分析发现:大鼠SUA水平与心肌Col I阳性面积百分比呈显著正相关。(3)与B组相比,C组SOD水平显著降低,D组则较C组显著升高;C组ox-LDL较B组明显升高,D组则较C组显著降低。单因素分析发现:SUA、心肌Col I阳性面积百分比均与血清ox-LDL呈显著正相关,与SOD呈显著负相关。多元回归分析显示SUA进入以Col I阳性面积百分比作为应变量的回归方程,所得回归方程为y=15.410+0.100x(y=心肌Col I阳性面积百分比,x=SUA,15.410为常数)。结论伴SUA升高的早期CKD大鼠存在心脏病理学改变,且病变严重程度与SUA水平呈正相关。氯沙坦可通过降低SUA水平,减轻氧化应激从而保护早期CKD大鼠心脏。
Objective To observe the effect of losartan on the heart disease of early chronic kidney disease (CKD) rats with elevated serum uric acid (SUA) and to explore the possible mechanism. Methods The experimental rats were randomly divided into three groups: sham operation group, sham operation group, sham operation group, sham operation group, sham operation group, sham operation group, CKD + losartan group: CKD + OXO + losartan), 15 in each group. SD rats were treated with right nephrectomy and OXO continuous gavage. The early CKD model was induced by SUA. The dosage of OXO was 800 mg · kg -1 · -1, twice a day. D group Losartan dose: 20mg · kg -1 · -1 times a day. After 16 weeks, the rats were sacrificed and serum creatinine (Scr), SUA, ox-LDL and SOD were measured. The pathological changes of renal tissue were observed by HE and PAS staining. The pathological changes of myocardium were observed. The expression of type I collagen (Col I) was detected by immunohistochemistry. Results (1) There was no significant difference in Scr level between the four groups. SUA in C group was significantly higher than the other three groups. Compared with the A group, the remaining three groups of renal tissue HE, PAS staining only mild mesangial proliferation. (2) There was no obvious morphological changes in HE staining of group A, and a small amount of myocardial Col I was deposited. There was a small amount of scattered inflammatory cells in the myocardial cells of group B, a small increase of Col I deposition. C group a large number of inflammatory cell infiltration, interstitial congestion, fibrosis; small blood vessels visible fibroblasts appear; Col I deposition increased significantly. Group D lesions were similar to group C, but the degree was significantly reduced. Only a small amount of inflammatory cells infiltrated, inflammatory cells were occasionally seen on the vessel wall, and Col I deposition was significantly reduced. Statistical analysis showed that: the percentage of myocardial Col I positive area in group C was significantly higher than that in group B, while that in group D was significantly lower than that in group C Univariate analysis showed that there was a significant positive correlation between SUA level and myocardial Col I positive area percentage. (3) Compared with group B, the level of SOD in group C was significantly lower than that in group C, while the level of ox-LDL in group C was significantly higher than that in group C and significantly lower in group D than that in group C. Univariate analysis showed that the percentages of positive area of SUA and myocardial Col I were positively correlated with serum ox-LDL and negatively correlated with SOD. Multiple regression analysis showed that SUA entered the regression equation with the percentage of Col I positive area as the dependent variable. The regression equation was y = 15.410 + 0.100x (y = the percentage of positive area of myocardial Col I, x = SUA, 15.410 was constant). Conclusion Early CKD rats with elevated SUA have pathological changes, and the severity of the disease is positively correlated with SUA level. Losartan can protect the heart of early CKD rat by reducing SUA level and reducing oxidative stress.