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 genomewide 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. Among diabetes mellitus nephropathy (DN) cases, intractable dysfunction rapidly propagating to end-stage renal disease often accompanies the nephrotic proteinuria phenotype. Our recent study implicated glypican-5 (GPC5) as a susceptible gene for acquired nephrotic syndrome and demonstrated its functional significance by using podocyte-specific knockout mice; a genome-wide association study of DN satisfying the criterion of nephrotic syndrome also clarified GPC5 as the candidate gene [odds ratio 1.45 (95% CI, 1.18e1.79)].

APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R

“…5c ). We induced podocyte injury in mice by administering basic fibroblast growth factor (bFGF) and puromycin aminonucleoside, which produce FSGS 30 . In this model (NPHS1-APOL1-G1-delta-RNA mice) (Fig.…”

“…Exclusion criteria were weight loss more than 20% during the experimental period. For proteinuria induction, mice (between 8 and 12 weeks old) were injected with bFGF and puromycin aminonucleoside, as previously described 30 . For NPHS1-APOL1-deltaRNA mice strain, puromycin aminonucleoside (Sigma-Aldrich) was injected subcutaneously at day 0 (200 mg per kg body weight), and bFGF (Kaken Pharmaceutical) was injected intravenously at days 0 and 2 (5 μg per animal), respectively.…”

Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

“…The direct involvement of podocyte proteoglycans for the proper function of the GFB was further documented by the development of nephrotic syndrome in the absence of these proteins [8,[29][30][31].…”

SHROOM3, the gene associated with chronic kidney disease, affects the podocyte structure

“…We evaluated the function of Shroom3 using siRNA and its in vivo delivery, TPFE. First, to investigate the proper ratio of TPFE to siRNA, we conducted a control experiment to obtain optimal conditions for knockdown Gpc5 in podocyte, the gene previously proved to be associated with nephrotic syndrome and localized in podocytes 13 , 14 . When si Gpc5 -TPFE complexes was injected at a base-pair ratio (R) of 10, no staining was shown in areas previously identified for Gpc5 staining with anti- Nephrin antibody in podocytes (Supplemental Figure 1 ).…”