南方医科大学学报

南方医科大学学报 ›› 2019, Vol. 39 ›› Issue (08): 944-.doi: 10.12122/j.issn.1673-4254.2019.08.11

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盐酸右旋美托咪啶通过提高HIF-1α的表达减轻糖尿病大鼠肾缺血再灌注损伤

季中华，王丽萍，王世英，梁根强   

  • 出版日期:2019-08-20 发布日期:2019-08-20

Dexmedetomidine hydrochloride up-regulates expression of hypoxia inducible factor-1α to alleviate renal ischemia-reperfusion injury in diabetic rats

  • Online:2019-08-20 Published:2019-08-20

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摘要： 目的本研究探讨盐酸右旋美托咪啶（Dex）是否通过提高HIF-1α的表达减轻糖尿病大鼠肾缺血再灌注后损伤。方法高 脂高糖饮食8周后的SD大鼠，30 mg/kg链脲佐菌素（STZ）腹腔注射，建立糖尿病大鼠模型。以大鼠双肾动脉结扎60 min再灌注 120 min 的方法制作肾缺血再灌注损伤模型。分为普通大鼠组（Con），假手术组（sham），普通大鼠肾缺血再灌注损伤模型组 （Con+I/R [ischemia-reperfusion, I/R]），普通大鼠肾缺血再灌注损伤模型Dex治疗组（Con+I/R+Dex），糖尿病大鼠组（DM），糖尿 病大鼠Dex治疗组（DM+Dex），糖尿病大鼠地高辛（Dig）灌胃组（DM+Dig），糖尿病大鼠肾缺血再灌注损伤模型组（DM+I/R），糖 尿病大鼠肾缺血再灌注损伤模型Dex治疗组（DM+I/R+Dex），糖尿病大鼠地高辛灌胃后肾缺血再灌注损伤模型Dex治疗组 （DM+Dig+I/R+Dex）。夹闭双肾动脉前2 h给予腹腔注射Dex，其它组别腹腔注射等量生理盐水。地高辛作为HIF-1α的抑制 剂，对于地高辛组予地高辛片0.05 mg/（kg· d）灌胃1周。所有组别大鼠肾缺血再灌注后取血样，分离血浆，多功能生化仪检测肌 酐（Scr）和尿素氮（BUN）含量，Western blot 测定HIF-1α、cleaved caspase-3、Bcl-2、Bax，ELISA 检测HIF-1α、p-eNOS、eNOS， TUNEL法测定肾小球细胞凋亡比例。结果普通大鼠和糖尿病大鼠在肾缺血再灌注后Scr、BUN、HIF-1α、p-eNOS、eNOS表达 水平及细胞凋亡比例均显著升高（P<0.05）；肾缺血再灌注损伤模型Dex治疗后Scr、BUN、p-eNOS、eNOS表达水平明显降低， HIF-1α表达水平明显升高，差异有统计学意义（P< 0.05）；与Con+I/R相比，DM+I/R组Scr、BUN、p-eNOS、eNOS进一步升高；与 DM+I/R组相比，DM+I/R+Dex组Scr、BUN、p-eNOS、eNOS、cleaved caspase-3、Bax表达水平及凋亡细胞比例明显降低，HIF-1α 及Bcl-2表达明显升高；与DM+I/R+Dex组相比，DM+Dig+I/R+Dex组cleaved caspase-3、Bax表达水平及凋亡细胞比例明显升 高，HIF-1α及Bcl-2表达水平显著下降。结论Dex可能通过提高2型糖尿病大鼠HIF-1α的表达，抑制肾脏细胞的凋亡，减轻肾脏 细胞缺血再灌注后损伤。

Abstract: Objective To verify whether dexmedetomidine hydrochloride (Dex) alleviates renal ischemia-reperfusion (IR) injury in diabetic rats by increasing the expression of hypoxia inducible factor-1α (HIF-1α). Methods A rat model of type 2 diabetes mellitus was established by high-fat diet and streptozotocin injection. The rats were subjected to daily intragastric administration of 0.05 mg/kg digoxin for 7 consecutive days and intraperitoneal injection of Dex 2 h before renal IR injury induced by ligation of the bilateral renal arteries for 60 min followed by reperfusion for 120 min. After reperfusion, blood samples were taken for detection of serum creatinine (Scr) and urea nitrogen (BUN) levels. Western blotting was used to detect the expression of HIF-1α, cleaved caspase- 3, Bcl-2, and Bax in the renal tissues; the expression of the HIF-1α, p-eNOS, and eNOS were detected using ELISA. The percentage of apoptotic glomerular cells was assessed using TUNEL assay. Results The levels of Scr, BUN, HIF-1α, p-eNOS, and eNOS and the percentage of apoptotic cells in both normal and diabetic rats increased significantly after renal IR injury (P<0.05). The expressions of Scr, BUN, p-eNOS, and eNOS decreased while HIF-1α expression increased significantly in Dex-treated rats with renal IR injury (P<0.05). Compared with the non-diabetic rats, the diabetic rats showed more obvious increase in the expressions of Scr, BUN, p-eNOS, and eNOS following renal IR injury. In the diabetic rats with renal IR injury, Dex treatment prior to the injury significantly lowered the expressions of Scr, BUN, p-eNOS, eNOS, cleaved caspase-3, and Bax, decreased the percentage of apoptotic cells, and increased the levels of HIF-1a and Bcl-2 (P<0.05). Digoxin treatment significantly antagonized the effects of Dex in the diabetic rats with renal IR injury by increasing the expressions of cleaved caspase-3 and Bax, promoting glomerular cell apoptosis, and decreasing renal expressions of HIF-1 and Bcl-2 (P<0.05). Conclusions Dex alleviates renal IR injury in diabetic rats probably by inhibiting renal expression of HIF-1α and glomerular cell apoptosis.