Cellular basis of diabetic nephropathy: V. Endoglin expression levels and diabetic nephropathy risk in patients with Type 1 diabetes.

摘要

Endoglin is an accessory receptor molecule that, in association with transforming growth factor beta (TGF-beta) family receptors Types I and II, binds TGF-beta1, TGF-beta3, activin A, bone morphogenetic protein (BMP)-2 and BMP-7, regulating TGF-beta dependent cellular responses. Relevant to diabetic nephropathy, endoglin, expressed in vascular endothelial and smooth muscle cells, fibroblasts, and mesangial cells, negatively regulates extracellular matrix (ECM). The aim of this study was to evaluate endoglin expression in cultured skin fibroblasts from patients with Type 1 diabetes with and without diabetic nephropathy. Kidney and skin biopsies were performed in 125 Type 1 diabetic patients. The 20 with the fastest rate of mesangial expansion (estimated by electron microscopy) and proteinuria ("fast-track") and the 20 with the slowest rate and normoalbuminuria ("slow-track"), along with 20 controls were studied. Endoglin mRNA expression was assessed by microarray and quantitative real-time polymerase chain reaction (QRT-PCR) and protein expression by Western blot. Age and sex distribution were similar among groups. Diabetes duration was similar (20+/-8 vs. 24+/-7 years), hemoglobin A1c lower (8.4+/-1.2% vs. 9.4+/-1.5%), and glomerular filtration rate higher (115+/-13 vs. 72+/-20 ml/min per 1.73 m2) in slow-track vs. fast-track patients. Microarray endoglin mRNA expression levels were higher in slow-track (1516.0+/-349.9) than fast-track (1211.0+/-274.9; P=.008) patients or controls (1223.1+/-422.9; P=.018). This was confirmed by QRT-PCR. Endoglin protein expression levels correlated with microarray (r=0.59; P=.044) and QRTPCR (r=0.61; P=.034) endoglin mRNA expression. These studies are compatible with the hypothesis that slow-track Type 1 diabetic patients, strongly protected from diabetic nephropathy, have distinct cellular behaviors that may be associated with reduced ECM production.