Parameswaran Narayanan, Hall Carolyn S, Bomberger Jennifer M, Sparks Harvey V, Jump Donald B, Spielman William S
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Kidney Blood Press Res. 2003;26(1):2-9. doi: 10.1159/000069764.
BACKGROUND/AIMS: Ciglitazone and other thiazolidinedione compounds are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and improve renal function in diabetic nephropathy independent of blood glucose control. Because interstitial fibroblasts and glomerular mesangial cells are important cell types affected in diabetic nephropathy, the major aim of the present study was to examine the effect of ciglitazone on apoptosis and growth of renal interstitial fibroblasts (NRKs) and glomerular mesangial cells (MMCs).
The effect of ciglitazone on apoptosis and cell growth of cultured NRKs and MMCs was done using DNA fragmentation and MTS cell-growth assays, respectively. The potential role of PPAR-gamma in these two cell types was examined by reporter gene analysis.
Ciglitazone induced caspase-dependent apoptosis of both NRKs and MMCs and caused a significant decrease in cell growth. Other PPAR-gamma ligands also mimicked this effect. Interestingly, ciglitazone did not activate the PPRE-TK-CAT (peroxisome proliferator regulatory element, a thymidine kinase promoter and a chloramphenicol acetyltransferase gene) when transfected into NRKs, suggesting that ciglitazone does not activate the endogenous PPAR-gamma system in NRKs. On the other hand, ciglitazone activated the endogenous PPAR-gamma in MMCs.
Apoptotic and negative growth effects of ciglitazone, in NRKs, are not mediated through PPAR-gamma. The thiazolidinediones have important cellular effects on renal interstitial fibroblasts and glomerular mesangial cells that may be therapeutically useful in non-diabetic renal disease.
背景/目的：西格列他唑及其他噻唑烷二酮类化合物是过氧化物酶体增殖物激活受体γ（PPAR-γ）配体，可在不依赖血糖控制的情况下改善糖尿病肾病患者的肾功能。由于肾间质成纤维细胞和肾小球系膜细胞是糖尿病肾病中受影响的重要细胞类型，本研究的主要目的是检测西格列他唑对肾间质成纤维细胞（NRK）和肾小球系膜细胞（MMC）凋亡及生长的影响。
分别采用DNA片段化分析和MTS细胞生长试验检测西格列他唑对培养的NRK和MMC凋亡及细胞生长的影响。通过报告基因分析检测PPAR-γ在这两种细胞类型中的潜在作用。
西格列他唑诱导NRK和MMC发生半胱天冬酶依赖性凋亡，并导致细胞生长显著降低。其他PPAR-γ配体也具有类似作用。有趣的是，将西格列他唑转染至NRK时，并未激活PPRE-TK-CAT（过氧化物酶体增殖物调节元件、胸苷激酶启动子和氯霉素乙酰转移酶基因），提示西格列他唑未激活NRK中的内源性PPAR-γ系统。另一方面，西格列他唑可激活MMC中的内源性PPAR-γ。
西格列他唑对NRK的凋亡及负生长作用并非通过PPAR-γ介导。噻唑烷二酮类化合物对肾间质成纤维细胞和肾小球系膜细胞具有重要的细胞作用，可能对非糖尿病肾病具有治疗作用。
