Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas.
Department of Pharmacology and Neuroscience, The North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas.
Am J Physiol Cell Physiol. 2022 Jul 1;323(1):C226-C235. doi: 10.1152/ajpcell.00359.2021. Epub 2022 Jun 15.
Neogenin, a transmembrane receptor, was recently found in kidney cells and immune cells. However, the function of neogenin signaling in kidney is not clear. Mesangial cells (MCs) are a major source of extracellular matrix (ECM) proteins in glomerulus. In many kidney diseases, MCs are impaired and manifest myofibroblast phenotype. Overproduction of ECM by the injured MCs promotes renal injury and accelerates the progression of kidney diseases. The present study aimed to determine if neogenin receptor was expressed in MCs and if the receptor signaling regulated ECM protein production by MCs. We showed that neogenin was expressed in the glomerular MCs. Deletion of neogenin using CRISPR/Cas9 lentivirus system significantly reduced the abundance of fibronectin, an ECM protein. Netrin-1, a ligand for neogenin, also significantly decreased fibronectin production by MCs and decreased neogenin protein expression in MCs. Furthermore, treatment of human MCs with high glucose (HG, 25 mM) significantly increased the protein abundance of neogenin as early as 8 h. Consistently, neogenin expression in glomerulus significantly increased in the eNOS diabetic mice starting as early as the age of 8 wk and this increase sustained at least to the age of 24 wk. We further found that the HG-induced increase in neogenin abundance was blunted by antioxidant PEG-catalase and N-acetyl cysteine. Taken together, our results suggest a new mechanism of regulation of fibronectin production by MCs. This previously unrecognized neogenin-fibronectin pathway may contribute to glomerular injury responses during the course of diabetic nephropathy.
Neogenin 是一种跨膜受体，最近在肾脏细胞和免疫细胞中被发现。然而，neogenin 信号在肾脏中的功能尚不清楚。系膜细胞（MCs）是肾小球中细胞外基质（ECM）蛋白的主要来源。在许多肾脏疾病中，MCs受损并表现出肌成纤维细胞表型。受损的 MCs 过度产生 ECM 会促进肾脏损伤并加速肾脏疾病的进展。本研究旨在确定 neogenin 受体是否在 MCs 中表达，以及受体信号是否调节 MCs 产生 ECM 蛋白。我们表明 neogenin 在肾小球 MCs 中表达。使用 CRISPR/Cas9 慢病毒系统敲除 neogenin 可显著降低 ECM 蛋白纤维连接蛋白的丰度。neogenin 的配体 netrin-1 也可显著降低 MCs 中纤维连接蛋白的产生，并降低 MCs 中 neogenin 蛋白的表达。此外，用高浓度葡萄糖（25mM）处理人 MCs 可使 neogenin 蛋白丰度在 8 小时内显著增加。同样，eNOS 糖尿病小鼠肾小球中 neogenin 的表达从 8 周龄开始显著增加，并且至少持续到 24 周龄。我们进一步发现，抗氧化剂 PEG-过氧化氢酶和 N-乙酰半胱氨酸可减弱 HG 诱导的 neogenin 丰度增加。综上所述，我们的研究结果表明了一种 MCs 调节纤维连接蛋白产生的新机制。这一未被认识的 neogenin-纤维连接蛋白途径可能有助于糖尿病肾病过程中肾小球损伤反应。
