Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome
Por:
Clement L.C., Avila-Casado C., MacÉ C., Soria E., Bakker W.W., Kersten S., Chugh S.S.
Publicada:
1 ene 2011
Resumen:
The main manifestations of nephrotic syndrome include proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. Common causes of nephrotic syndrome are diabetic nephropathy, minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) and membranous nephropathy. Among the primary glomerular diseases, MCD is usually sensitive to glucocorticoid treatment, whereas the other diseases show variable responses1. Despite the identification of key structural proteins in the glomerular capillary loop which may contribute to defects in ultrafiltration, many of the disease mechanisms of nephrotic syndrome remain unresolved. In this study, we show that the glomerular expression of angiopoietin-like-4 (Angptl4), a secreted glycoprotein, is glucocorticoid sensitive and is highly upregulated in the serum and in podocytes in experimental models of MCD and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range, and selective, proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, whereas transgenic expression specifically in the adipose tissue (aP2-Angptl4) resulted in increased circulating Angptl4, but no proteinuria. Angptl4-/- mice that were injected with lipopolysaccharide (LPS) or nephritogenic antisera developed markedly less proteinuria than did control mice. Angptl4 secreted from podocytes in some forms of nephrotic syndrome lacks normal sialylation. When we fed the sialic acid precursor N-acetyl-D-mannosamine (ManNAc) to NPHS2-Angptl4 transgenic rats it increased the sialylation of Angptl4 and decreased albuminuria by more than 40%. These results suggest that podocyte-secreted Angptl4 has a key role in nephrotic syndrome. © 2011 Nature America, Inc. All rights reserved.
Filiaciones:
Clement L.C.:
Glomerular Disease Therapeutics Laboratory, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
Avila-Casado C.:
Department of Pathology, Instituto Nacional de Cardiología, Mexico City, Mexico
MacÉ C.:
Glomerular Disease Therapeutics Laboratory, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
Soria E.:
Department of Pathology, Instituto Nacional de Cardiología, Mexico City, Mexico
Bakker W.W.:
Department of Pathology and Medical Biology, University Medical Center of Groningen, Groningen, Netherlands
Kersten S.:
Division of Human Nutrition, Wageningen University, Wageningen, Netherlands
Chugh S.S.:
Glomerular Disease Therapeutics Laboratory, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL, United States
|