Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney
Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney
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DOI：
10.1152/ajprenal.00205.2007
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发表时间：
2007-10-01
影响因子：
4.2
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
--
作者：
Sawai, Kazutomo;Mukoyama, Masashi;Nakao, Kazuwa
CCN1（半胱氨酸富蛋白61；Cyr61）是一种细胞外基质相关的信号分子，在细胞迁移、粘附和分化中起作用。我们之前报道了CCN1在大鼠抗thy -1肾小球肾炎（一种众所周知的可逆性肾小球损伤模型）的足细胞中被诱导，但其在人类肾脏中的表达和意义仍然完全未知（Sawai K, Mori K, Mukoyama M, Sugawara a, Suganami T, Koshikawa M, Yahata K, Makino H, Nagae T, Fujinaga Y, Yokoi H, Yoshioka T, Yoshimoto a, Tanaka I, Nakao K. J Am Soc Nephrol 14: 154-1163, 2003）。在这里，我们报道，在人肾脏中，CCN1的表达仅限于正常成人肾小球和毛细血管环期的胚胎肾小球的足细胞。足细胞CCN1表达在IgA肾病、糖尿病肾病和膜性肾病中降低，而在微小变化疾病和局灶节段性肾小球硬化中保持不变。CCN1的下调在肾小球系膜严重扩张的病变肾脏中更为明显。CCN1蛋白也定位于Henle’s袢的厚升肢、远端和近端小管以及集合管，在病变肾脏中未见改变。在体外，重组CCN1蛋白增强内皮细胞粘附，而显著抑制系膜细胞粘附。CCN1也完全抑制系膜细胞迁移，提示其作为系膜排斥因子的作用。在培养的足细胞中，CCN1以剂量依赖性方式显著诱导细胞周期蛋白依赖性激酶抑制剂p27（Kip1）和synaptopodin的表达，并抑制足细胞迁移。这些数据表明，CCN1在足细胞中表达，可作用于肾小球细胞调节肾小球重塑，并在病变肾脏中下调，提示足细胞中CCN1表达受损可能有助于肾小球疾病伴系膜扩张的进展。
CCN1 (cysteine-rich protein 61; Cyr61) is an extracellular matrix-associated signaling molecule that functions in cell migration, adhesion, and differentiation. We previously reported that CCN1 is induced at podocytes in rat anti-Thy-1 glomerulonephritis, a well-known model of reversible glomerular injury, but its expression and significance in the human kidney remain totally unknown (Sawai K, Mori K, Mukoyama M, Sugawara A, Suganami T, Koshikawa M, Yahata K, Makino H, Nagae T, Fujinaga Y, Yokoi H, Yoshioka T, Yoshimoto A, Tanaka I, Nakao K. J Am Soc Nephrol 14: 1154-1163, 2003). Here we report that, in the human kidney, CCN1 expression was confined to podocytes in normal adult and embryonic glomeruli from the capillary loop stage. Podocyte CCN1 expression was decreased in IgA nephropathy, diabetic nephropathy, and membranous nephropathy, whereas it remained unchanged in minimal change disease and focal segmental glomerulosclerosis. Downregulation of CCN1 was significantly greater in diseased kidneys with severe mesangial expansion. CCN1 protein was also localized in the thick ascending limb of Henle's loop, distal and proximal tubules, and collecting ducts, which was not altered in diseased kidneys. In vitro, recombinant CCN1 protein enhanced endothelial cell adhesion, whereas it prominently inhibited mesangial cell adhesion. CCN1 also completely suppressed mesangial cell migration, suggesting its role as a mesangial-repellent factor. In cultured podocytes, CCN1 markedly induced the expression of cyclin-dependent kinase inhibitor p27(Kip1) as well as synaptopodin in a dose-dependent manner and suppressed podocyte migration. These data indicate that CCN1 is expressed in podocytes, can act on glomerular cells to modulate glomerular remodeling, and is downregulated in diseased kidneys, suggesting that impairment of CCN1 expression in podocytes may contribute to the progression of glomerular disease with mesangial expansion.