Okamoto Koji, Honda Kenjiro, Doi Kent, Ishizu Tomoko, Katagiri Daisuke, Wada Takehiko, Tomita Kenji, Ohtake Takayasu, Kaneko Toyoji, Kobayashi Shuzo, Nangaku Masaomi, Tokunaga Katsushi, Noiri Eisei
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.
Department of Nephrology, Endocrinology, Hemodialysis & Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan.
Am J Pathol. 2015 Jul;185(7):1889-98. doi: 10.1016/j.ajpath.2015.03.025. Epub 2015 May 15.
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.
2型糖尿病是全球主要的健康问题。在糖尿病肾病（DN）病例中，2型糖尿病的主要并发症，肾病表型通常对临床干预难以处理，并显示肾功能迅速下降至终末期肾病。我们最近鉴定出硫酸乙酰肝素蛋白聚糖5（GPC5）基因，一种细胞表面硫酸乙酰肝素蛋白聚糖，可导致获得性肾病综合征的易感性，并通过全基因组关联研究进一步确定了GPC5中的一个变体与2型糖尿病的DN之间的关联。体内和体外数据显示，在2型DN中，GPC5随着病情严重程度逐渐增加；其过量表达源自肾小球系膜细胞。在本研究中，糖尿病肾病显示成纤维细胞生长因子（Fgf）2的积累显著诱导进行性蛋白尿，而在Gpc5基因敲低小鼠中可避免这种情况。Gpc5抑制的效果通过糖尿病肾病中Fgf受体3和4的表达间接发挥作用。肾小球外Fgf2在DN中具有致病性，而抑制Gpc5可有效抑制Fgf2在肾小球的积累、随后系膜细胞外基质的增加以及足细胞的小GTP酶活性。这些发现阐明了在全基因组关联研究中被鉴定为易感基因的GPC5在高血糖诱导的肾小球病中的关键作用。
