Endoglin is an accessory receptor molecule that, in association with transforming growth factor β (TGF-β) family receptors Types I and II, binds TGF-β1, TGF-β3, activin A, bone morphogenetic protein (BMP)-2 and BMP-7, regulating TGF-β 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 QRT-PCR (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.
Bibliographical noteFunding Information:
Patricia Alvarez-Muñoz is a fellow from the Ministerio de Educación y Ciencia, Spain. Dr. M. Luiza Caramori was previously supported by a Research Fellowship grant from the Juvenile Diabetes Research Foundation International (JDRFI) and is currently a JDRFI Career Development Award recipient. This work was supported by grants from the National Institutes of Health (DK13083, DK54638 and DK070210), National Center for Research Resources (M01-RR00400), Spanish Ministerio de Ciencia y Tecnología (BFU2004-00285/BFI) and Instituto de Salud Carlos III (ISCIII-RETIC RD/0016/0002). We thank Dr. Francisco Sanchez-Madrid for the gift of TEA 1/58 antibody. We thank Messrs. John Basgen and Thomas Groppoli for performing the morphometric studies and Ms. Kim Pinkham and Mr. Paul Walker for assisting with the cellular studies.
- Diabetic nephropathy
- Type 1 diabetes