罗格列酮保护大鼠重症急性胰腺炎肾损伤的机制

Protective mechanism of rosiglitazone on renal injury of severe acute pancreatitis

目的探讨高选择性过氧化物酶体增殖物激活受体-1（PPAR-γ）的激动剂罗格列酮（ROSI）保护大鼠重症急性胰腺炎（SAP）肾损伤的可能机制。方法将雄性Wistar大鼠54只随机分为假手术组（s0组）、重症急性胰腺炎组（SAP组）和罗格列酮处理组（ROSI组），每组大鼠18只。胆胰管逆行注射5％牛磺胆酸钠制备重症急性胰腺炎模型。ROSI组造模前30rain经股静脉注射10％二甲基亚砜（DMSO）溶解的罗格列酮（6mg／kg）；SO组、SAP组则经股静脉注射等量10％DMSO（0．2ml／100g）。术后3、12、24h分批剖杀大鼠，每个时间点6只。分别取肾组织检测一氧化氮（NO）及其合成酶（iNOS）的水平和核转录因子-KB（NF—KB）／p65蛋白表达水平，并观察不同时间点组大鼠肾脏肿瘤坏死因子-a（TNF-a）和细胞间黏附分子-1（ICAM-1）的mRNA及蛋白表达。结果SAP组各时点NO含量分别为（2．34±0．31）、（7．73±0．48）、（17．33±0．89）mg／g；SAP组各时点NF．KB／p65含量分别为30648．11±2655．13、53654．63±3065．94、70546．85±5046．55；SAP组各时点TNF—a表达水平为4．18±0．61、5．69±0．82、11．86±2．49；SAP组各时点ICAM-1表达水平为3．68±0．58、6．48±0．76、8．62±1．09，均与S0组各时间点比较显著升高，差异有统计学意义（P〈0．05）；ROSI组12、24h时点NO含量分别为（4．10±0．62）、（6．09±0．79）mg／g；ROSI组24h时点NF—KB／p65含量为30468．48±2684．59；ROSI组24h时点TNF-a表达水平为6．60±1．34；ROSI组24h时点ICAM-1表达水平为2．92±0．88，均较SAP组下降，差异有统计学意义（P〈0．05）。结论罗格列酮通过抑制NF-KB的表达，从而减少TNF-和ICAM-1的产生，减轻炎症反应的发生发展，显示其参与了保护重症急性胰腺炎所诱发的肾损伤机制。

Objective To investigate the protective mechanism of rosiglitazone, the highly selec-tive peroxisome proliferator activated receptor-γ（PPAR-γ） agonist, on renal injury of rats with severe acute pancreatitis （SAP）. Methods Fifty-four male Wistar rats were randomly divided into three groups： sham operation group （SO group）, SAP group and rosiglitazone pretreatment group （ROSI group）. Acute panereatitis model was induced by retrograde infusion of 5% sodium taurocholate into the biliopancreatic duct. Rosiglitazone （6 mg/kg） dissolved in 10% DMSO were injected through the femoral vein 30 rain piror to the operation. The rats in SO group and SAP group were injected partes aequales 10% DMSO. Rats were sacrificed at 3, 12 and 24 h after operation, then the contents of nitric oxide （NO） and inducible ni- tric oxide synthase （iNOS）, the levels of nuclear factor-KB （NF-KB）/p65, and tumor necrosis factor （TNF）-a and intercellular adhesion molecule-1 （ICAM-1） mRNA/proteins of kidney tissue samples were measured and analyzed statistically. Results At 3, 12 and 24 h after operation in SAP group, the contents of NO was （2.34±0.31）, （7.73 ±0.48）, （17.33 ±0.89） mg/g; the levels of NF-KB/p65 was （30 648. 11 _＋ 2655. 13 ）, （ 53 654. 63 _＋ 3065.94 ）, （ 70 546. 85 _＋ 5046. 55 ） ; the level of TNF-c~ was 4. 18 ＋0. 61, 5.69 ±0. 82, 11.86 ＋2. 49; the level of ICAM-1 was 3.68 ＋-0. 58, 6. 48 ±0. 76, 8. 62 ＋ 1.09, respectively, all were significantly increased （P 〈 0.05 ） aas compared with SO group. In ROSI group, the contents of NO at 12 and 24 h were （4. 10±0.62） and （6.09 ＋0.79） mg/g; the level of NF-KB/p65 at 24 h was 30468.48±2684. 59 ; the level of TNF-a at 24 h was 6. 60 ± 1.34 ; the level of ICAM-1 at 24 h was 2. 92±0. 88, which were significantly reduced as compared with SAP group （ P 〈 0. 05）. Conclusion Rosiglitazone protects rats with SAP from renal injury with the mechanisms involving inhibiting NF-KB and then inhibiting TNF-a and ICAM-1 production, thereby repressing the development of inflammation.