title: Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome.
abstract: 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. 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.
authors.affiliation: Glomerular Disease Therapeutics Laboratory, and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Lionel C
authors.initials: LC
authors.lastname: Clement
authors.forename: Carmen
authors.initials: C
authors.lastname: Avila-Casado
authors.forename: Camille
authors.initials: C
authors.lastname: Macé
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Soria
authors.forename: Winston W
authors.initials: WW
authors.lastname: Bakker
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Sumant S
authors.initials: SS
authors.lastname: Chugh
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009404:Nephrotic Syndrome / Q000503:physiopathology / Q000652:urine*; D011507:Proteinuria / Q000235:genetics / Q000517:prevention & control*; D051381:Rats; D055647:Rats, Transgenic
chemical_list: C528241:ANGPTL4 protein, rat; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse