Sanai T, Sobka T, Johnson T, el-Essawy M, Muchaneta-Kubara E C, Ben Gharbia O, el Oldroyd S, Nahas A M
Sheffield Kidney Institute, Northern General Hospital Trust, UK.
Diabetologia. 2000 Jan;43(1):91-100. doi: 10.1007/s001250050012.
AIMS/HYPOTHESIS: Diabetic nephropathy is characterised by structural changes known to be associated in non-diabetic nephropathies with the expression of the cytoskeletal proteins a-smooth muscle actin and vimentin. We aimed to investigate the expression of cytoskeletal proteins in experimental diabetic nephropathy.
Rats were made diabetic by an injection of streptozotocin (45 mg/kg). Groups of rats (n = 6) and their respective controls (n = 4) were killed at different time intervals. (days 7, 15, 30, 60, 90 and 120). We also studied two groups of diabetic rats treated with a long-acting insulin; the first (n = 8) was treated from the induction of diabetes and the second (n = 8) received insulin from day 15 onward. At each time-point, kidney function, proteinuria and histology were evaluated. Cytoskeletal proteins and collagens III and IV deposition was determined by immunohistochemistry. Changes in the transcription of the cytoskeletal proteins was determined by northern blot analysis.
Although normal glomeruli did not express alpha-smooth muscle actin until late in the time course, it was detected in diabetic mesangium from day 7 onward. In the interstitium, it appeared in a perivascular and peritubular distribution. Vimentin was detectable within normal glomerular epithelial cells and increased rapidly (days 7 and 15) in diabetic rats. Vimentin also appeared early within the lining of the peritubular capillaries and damaged diabetic tubules. These changes were associated with a delayed increased transcription of alpha-smooth muscle actin and vimentin. Treatment with insulin (early or late) attenuated and reversed respectively the expression of cytoskeletal proteins and collagens within diabetic kidneys. Close correlations were noted between the number of alpha-smooth muscle actin positive cells within diabetic glomeruli and mesangial expansion (r = 0.46, p < 0.02) as well as interstitial alpha-smooth muscle actin positive cells and interstitial fibrosis (r = 0.51, p < 0.002).
CONCLUSION/INTERPRETATION: Changes in the expression of cytoskeletal proteins within the kidneys of diabetic rats suggest a role for alpha-smooth muscle actin and vimentin in the pathogenesis of diabetic kidney disease.
目的/假设：糖尿病肾病的特征是出现一些结构变化，这些变化在非糖尿病肾病中已知与细胞骨架蛋白α-平滑肌肌动蛋白和波形蛋白的表达有关。我们旨在研究实验性糖尿病肾病中细胞骨架蛋白的表达情况。
通过注射链脲佐菌素（45mg/kg）使大鼠患糖尿病。将大鼠分组（每组n = 6），并在不同时间间隔（第7、15、30、60、90和120天）处死，同时处死各自的对照组（每组n = 4）。我们还研究了两组用长效胰岛素治疗的糖尿病大鼠；第一组（n = 8）从糖尿病诱导期开始治疗，第二组（n = 8）从第15天起接受胰岛素治疗。在每个时间点，评估肾功能、蛋白尿和组织学情况。通过免疫组织化学法测定细胞骨架蛋白以及III型和IV型胶原蛋白的沉积。通过Northern印迹分析确定细胞骨架蛋白转录的变化。
尽管正常肾小球直到病程后期才表达α-平滑肌肌动蛋白，但从第7天起在糖尿病肾小球系膜中就能检测到。在间质中，它呈血管周围和肾小管周围分布。波形蛋白在正常肾小球上皮细胞内可检测到，并且在糖尿病大鼠中迅速增加（第7天和第15天）。波形蛋白在肾小管周围毛细血管内衬和受损的糖尿病肾小管中也早期出现。这些变化与α-平滑肌肌动蛋白和波形蛋白转录的延迟增加有关。胰岛素治疗（早期或晚期）分别减轻并逆转了糖尿病肾脏中细胞骨架蛋白和胶原蛋白的表达。糖尿病肾小球内α-平滑肌肌动蛋白阳性细胞数量与系膜扩张之间（r = 0.46，p < 0.02）以及间质α-平滑肌肌动蛋白阳性细胞与间质纤维化之间（r = 0.51，p < 0.002）存在密切相关性。
结论/解读：糖尿病大鼠肾脏中细胞骨架蛋白表达的变化表明α-平滑肌肌动蛋白和波形蛋白在糖尿病肾病发病机制中起作用。
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