Gong Eun-Yeung, Jo Hyung Ah, Park Sang Hyun, Cha Dae Ryong, Hur Dae Young, Han Sang Youb
Department of Anatomy and Tumor Immunology, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan 47392, Korea.
Department of Internal Medicine, Inje University College of Medicine, Ilsan-Paik Hospital, Joowha-ro 170, IlsanSeo-gu, Goyang, Gyeonggi 10380, Korea.
Life (Basel). 2020 Dec 17;10(12):354. doi: 10.3390/life10120354.
High glucose-mediated tubular injury contributes to the development and progression of diabetic nephropathy through renal tubulointerstitial fibrosis. V-set immunoglobulin-domain-containing 4 (VSIG4), a B7 family-related protein, is a complement receptor. Although the role of epithelial-mesenchymal transition (EMT) has been reported in several diseases, little is known about its relationship with VSIG4 under diabetic conditions. This study aimed to investigate the role of VSIG4 in human tubule cells stimulated by high glucose (HG, 55 mM). HG upregulated both mRNA and protein levels of VSIG4 in proximal tubule cells (HK-2 cells) and Madin Darby Canine Kidney cells. These upregulations were accompanied by increased expression of mesenchymal markers such as fibronectin, N-cadherin, matrix metalloproteinase 9, and vimentin, and by decreased expression of the epithelial marker, E-cadherin. The siRNA-mediated inhibition of VSIG4 in HK-2 cells restored the dysregulation of EMT in cells. Interestingly, VSIG4 inhibition did not affect the expression of transforming growth factor (TGF)-β, whereas inhibition of TGF-β reduced VSIG4 expression, subsequently suppressing fibrosis markers. These findings suggest that VSIG4 plays an important role in mediating renal tubular EMT through the downstream action of HG-induced TGF-β activation.
高糖介导的肾小管损伤通过肾小管间质纤维化促进糖尿病肾病的发生和发展。含V-set免疫球蛋白结构域4（VSIG4）是一种B7家族相关蛋白，是一种补体受体。尽管上皮-间质转化（EMT）在多种疾病中的作用已有报道，但在糖尿病条件下其与VSIG4的关系却知之甚少。本研究旨在探讨VSIG4在高糖（HG，55 mM）刺激的人肾小管细胞中的作用。高糖上调近端肾小管细胞（HK-2细胞）和犬肾细胞中VSIG4的mRNA和蛋白水平。这些上调伴随着间充质标志物如纤连蛋白、N-钙黏蛋白、基质金属蛋白酶9和波形蛋白表达的增加，以及上皮标志物E-钙黏蛋白表达的降低。HK-2细胞中siRNA介导的VSIG4抑制恢复了细胞中EMT的失调。有趣的是，VSIG4抑制并不影响转化生长因子（TGF）-β的表达，而TGF-β抑制则降低VSIG4表达，随后抑制纤维化标志物。这些发现表明，VSIG4通过HG诱导的TGF-β激活的下游作用在介导肾小管EMT中起重要作用。
