罗格列酮对肾大部切除大鼠残肾细胞外基质的影响及其机制

目的：观察罗格列酮对肾大部切除大鼠残肾的细胞外基质（ECM）的影响并探讨其可能的机制。方法：将大鼠随机分为4组，每组8只：假手术组（SHAM组）、肾大部切除组（NX组）、肾大部切除加小剂量罗格列酮治疗组（XL组，罗格列酮5mg.kg^-1·d^-1）和肾大部切除加大剂量罗格列酮治疗组（DL组，罗格列酮15mg·kg^-1·d^-1）。8周后观察大鼠尿蛋白、血BUN、Scr和肾脏病理改变，用免疫组化检测基质金属蛋白酶-2（MMP-2）、基质金属蛋白酶-9（MMP-9）在肾组织中的表达。用天狼星红染色半定量法检测肾脏胶原纤维含量。用RT～PCR的方法测定肾组织中纤连蛋白（FN）的表达。结果：（1）罗格列酮能降低大鼠24h尿蛋白定量、血BUN、Scr，与NX组比较有统计学差异（P〈0.01，P〈0．05）。（2）NX组可见肾小球硬化，ECM增生，肾组织大量胶原纤维沉积。用药后病变减轻，其中大剂量罗格列酮组肾小球MMP-2明显增多；肾小管、间质MMP-9明显减少；肾小球囊壁、肾小球基底膜及肾小管基底膜、血管周围胶原纤维沉积减少。（3）与SHAM组相比，NX组残肾组织FN mRNA的表达均明显升高（P〈0.05），XL组FN mRNA的表达较NX组有所降低，以大剂量XL组为明显（P〈0．01）。结论：罗格列酮可剂量依赖性地降低尿蛋白，改善肾功能肾脏病理损害；减少肾脏胶原纤维沉积和FN的表达；这可能与罗格列酮能抑制肾组织MMP-9表达和上调MMP-2表达有关。

Effects and Mechanism of Rosiglitazone on the Expression of Extracellular Matrix on Rat Remnant Kidney

Objective：To investigate the effects of rosiglitazone on the expression of extracellular matrix on rats with subto- tal renal ablation, and explore its mechanism. Methods-Rats were randomly assigned to four groups with 8 animals in each group： sham - operated （SHAM） group, subtotal renal ablation （NX） group, NX treated with rosiglitazone （ 5 mg.kg^-1. d^-1 ） （ XL group ）, NX treated with rosiglitazone （ 15 mg. kg^-1. d^-1 ） （DL group）. The urinary protein, BUN and serum creatinine（Scr） were measured after 8 weeks, renal pathological changes were evaluated. The expression of matrix metalloproteinase - 2（ MMP - 2） and matrix metalloproteinase- 9（MMP- 9） were detected by way of immunohistochemistry. Renal mesangial collagen fibers were stained with Pieric acid - Sirius red. The expression of FN were detected by way of RT - PCR. Results： （ 1）Compared with the NX group,24 hours urinary protein, BUN, serum creatinine（Ser） of Rosiglitazone treatment groups rats were substantially decreased, （P 〈 0.05 ）. （2） Pathohistological study revealed that, compared with the NX group, there were less glomerular matris, collagen and fibronectin in Rosiglitazone treatment groups. Among the subtotal nephrectomy rats, DL group had the least renal changes in collagen and fibronectin dpesition. There were less MMP - 9 in DL group than those in NX group. There were more MMP - 2 in DL group than those in NX group. （3）The levels of FN mRNA in all experimental groups rats were remarkably less than those in NX group. Conelusion： （1）Rosiglitazone can reduce 24 hours urinary protein, BUN, serum creatinine（Scr） and improve renal historical damage. （2） Rosiglitazone can decrease the level of FN mRNA and reduce renal extracellular matrix accumulation.on rats with subtotal renal ablation and significantly prevents renal injury. （3）Rosiglitazone can inhibit MMP - 9, increase MMP - 2. Rosiglitazone significantly prevents renal injury following subtotal renal ablation.