慢性间歇性低氧激活内质网应激介导大鼠肾脏损伤

Chronic intermittent hypoxia induces renal injury in rats by activating endoplasmic reticulum stress

目的探讨慢性间歇性低氧在普通饮食及高脂饮食引起肾脏损伤中的作用机制。方法将SPF级健康雄性Wistar大鼠24只,随机分为4组(每组6只),分别为A组(常氧并普通饮食)、B组(常氧并高脂饮食)、C组(慢性间歇性低氧并普通饮食)和D组(慢性间歇性低氧并高脂饮食)。6周后检测血清中肾脏早期损伤指标半胱氨酸蛋白酶抑制剂C(Cys-C),行肾脏CHOP蛋白免疫组化,并在电镜下观察肾小球及肾小管超微结构变化。结果 B组、C组、D组中肾早损指标Cys-C水平较A组显著升高,且在D组中值最高(均P<0.05);B组、C组、D组中内质网应激标志性蛋白CHOP平均光密度值与A组比较显著升高,且在D组中值最高(均P<0.05)。电镜下观察,A组肾小球及肾小管未见明显异常;B组、C组近曲肾小管上皮细胞局灶性核固缩,刷状缘稀疏并脱落;D组中有大片肾小管上皮细胞核固缩,刷状缘稀疏并脱落。结论慢性间歇性低氧、高脂饮食可通过激活内质网应激介导近曲肾小管上皮的凋亡,使肾脏的超微结构发生改变,进而导致肾脏功能损伤。

Objective To explore the mechanism of chronic intermittent hypoxia （CIH） on renal damage with normal diet and high-fat diet. Methods Twenty-four healthy male Wistar rats of SPF grade were randomly divided into 4 groups （n=6 in each group）, namely group A （normoxia and common diet）, group B （normoxia and high fat diet）, Group C （CIH and common diet）, and group D （CIH and high fat diet）. The serum cystatin C （Cys-C） was measured and the renal CHOP protein was detected by immunohistochemistry. The ultrastructural changes of glomeruli and renal tubules were observed under electron microscope. Results The levels of Cys-C in group B, group C and group D were significantly higher than those in group A （P〈0.05）. The mean density of endoplasmic reticulum stress （ERS） marker protein CHOP in group B, group C and group D was significantly higher than that in group A （P〈0.05）. Electron microscope revealed focal nuclear pyknosis in the partly renal tubular epithelial cells, sparse and scattered brush border in group B and group C, also revealed nuclear pyknosis in a large number of tubular epithelial cells, sparse and scattered brush border in group D. Conclusion CIH can activate the ERS mediated renal tubular epithelial apoptosis, thus induce ultrastructure changes and damage of kidney.