title: Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney.
abstract: Type 2 diabetes mellitus is a leading health issue worldwide. Among cases of diabetes mellitus nephropathy (DN), the major complication of type 2 diabetes mellitus, the nephrotic phenotype is often intractable to clinical intervention and demonstrates the rapid decline of renal function to end-stage renal disease. We recently identified the gene for glypican-5 (GPC5), a cell-surface heparan sulfate proteoglycan, as conferring susceptibility for acquired nephrotic syndrome and additionally identified an association through a genome-wide association study between a variant in GPC5 and DN of type 2 diabetes mellitus. In vivo and in vitro data showed a progressive increase of GPC5 in type 2 DN along with severity; the excess was derived from glomerular mesangial cells. In this study, diabetic kidney showed that accumulation of fibroblast growth factor (Fgf)2 strikingly induced progressive proteinuria that was avoided in Gpc5 knockdown mice. The efficacy of Gpc5 inhibition was exerted through expression of the Fgf receptors 3 and 4 provoked in the diabetic kidney attributively. Extraglomerular Fgf2 was pathogenic in DN, and the deterrence of Gpc5 effectively inhibited the glomerular accumulation of Fgf2, the subsequent increase of mesangial extracellular matrix, and the podocytes' small GTPase activity. These findings elucidate the pivotal role of GPC5, identified as a susceptible gene in the genome-wide association study, in hyperglycemia-induced glomerulopathy.
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Honda
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizu
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Katagiri
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Wada
authors.affiliation: Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Nephrology, Immunology, and Vascular Medicine, Shonan Kamakura General Hospital, Kamakura, Japan.
authors.forename: Takayasu
authors.initials: T
authors.lastname: Ohtake
authors.affiliation: Technology Advancement Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Toyoji
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Department of Nephrology, Immunology, and Vascular Medicine, Shonan Kamakura General Hospital, Kamakura, Japan.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan. Electronic address: noiri-tky@umin.ac.jp.
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004198:Disease Susceptibility; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005920:Glomerular Mesangium / Q000473:pathology; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009404:Nephrotic Syndrome / Q000209:etiology* / Q000473:pathology; D050199:Podocytes / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology; D051381:Rats
chemical_list: D053673:Glypicans; C501209:Gpc5 protein, mouse; D016222:Fibroblast Growth Factor 2