Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome
| Autor: | Elizabeth Soria, Lionel C. Clement, Winston W Bakker, Sander Kersten, Camille Macé, Carmen Avila-Casado, Sumant S. Chugh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Nephrotic Syndrome
030232 urology & nephrology urologic and male genital diseases Podocyte Diabetic nephropathy Mice Voeding Metabolisme en Genomica 0302 clinical medicine Minimal change disease Mice Knockout 0303 health sciences target gene Glomerular basement membrane apoptosis General Medicine female genital diseases and pregnancy complications Metabolism and Genomics 3. Good health Proteinuria medicine.anatomical_structure Metabolisme en Genomica Nutrition Metabolism and Genomics medicine.symptom Rats Transgenic medicine.medical_specialty Biology General Biochemistry Genetics and Molecular Biology Article oligomerization 03 medical and health sciences Membranous nephropathy Voeding Internal medicine medicine Albuminuria Angiopoietin-Like Protein 4 Animals Humans Lipiduria 030304 developmental biology VLAG Nutrition urogenital system medicine.disease gene-expression Rats Disease Models Animal Endocrinology Nephrotic syndrome Angiopoietins |
| Zdroj: | Nature medicine Nature Medicine, 17(1), 117-122 Nature Medicine, 17(1), 117-U294. Nature Publishing Group Nature Medicine 17 (2011) 1 |
| ISSN: | 1078-8956 |
| DOI: | 10.1038/nm.2261 |
| Popis: | 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 responses(1). 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. |
| Databáze: | OpenAIRE |
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