title: Heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, regulate glomerular integrity by modulating growth factor signaling.
abstract: Glomerular integrity and functions are maintained by growth factor signaling. Heparan sulfate, the major component of glomerular extracellular matrixes, modulates growth factor signaling, but its roles in glomerular homeostasis are unknown. We investigated the roles of heparan sulfate 6-O-endosulfatases, sulfatase (Sulf)1 and Sulf2, in glomerular homeostasis. Both Sulf1 and Sulf2 were expressed in the glomeruli of wild-type (WT) mice. Sulf1 and Sulf2 double-knockout (DKO) mice showed glomerular hypercellularity, matrix accumulation, mesangiolysis, and glomerular basement membrane irregularity. Platelet-derived growth factor (PDGF)-B and PDGF receptor-β were upregulated in Sulf1 and Sulf2 DKO mice compared with WT mice. Glomeruli from Sulf1 and Sulf2 DKO mice in vitro stimulated by either PDGF-B, VEGF, or transforming growth factor-β similarly showed reduction of phospho-Akt, phospho-Erk1/2, and phospho-Smad2/3, respectively. Since glomerular lesions in Sulf1 and Sulf2 DKO mice were reminiscent of diabetic nephropathy, we examined the effects of Sulf1 and Sulf2 gene disruption in streptozotocin-induced diabetes. Diabetic WT mice showed an upregulation of glomerular Sulf1 and Sulf2 mRNA by in situ hybridization. Diabetic DKO mice showed significant increases in albuminuria and serum creatinine and an acceleration of glomerular pathology without glomerular hypertrophy; those were associated with a reduction of glomerular phospho-Akt. In conclusion, Sulf1 and Sulf2 play indispensable roles to maintain glomerular integrity and protective roles in diabetic nephropathy, probably by growth factor modulation.
authors.affiliation: Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Takashima
authors.affiliation: Molecular Neurobiology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; and.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Keino-Masu
authors.affiliation: Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yashiro
authors.affiliation: Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hara
authors.affiliation: Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;
authors.forename: Tomo
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Matrix Biochemistry, Nijmegen Center for Molecular Life Sciences, Radbout University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Molecular Neurobiology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; and.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Masu
authors.affiliation: Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; nagatam@md.tsukuba.ac.jp.
authors.forename: Michio
authors.initials: M
authors.lastname: Nagata
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006497:Heparan Sulfate / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D013429:Sulfatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D006497:Heparan Sulfate; D036341:Intercellular Signaling Peptides and Proteins; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D017978:Receptors, Growth Factor; D051896:Smad Proteins, Receptor-Regulated; D013429:Sulfatases; D015238:Sulfotransferases; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C486773:Sulf1 protein, mouse; C514911:Sulf2 protein, mouse
keywords: diabetic nephropathy; heparan sulfate; platelet-derived growth factor; sulfatase; sulfatase 1; sulfatase 2