Progranulin is a secreted glycoprotein expressed in neurons and microglial cells that is involved in maintaining physiological functions. Many studies have found that progranulin may play a protective role against ischemic brain injury, but little is known about how the expression level and cellular localization status of progranulin is regulated after hypoxia–ischemia. Research has confirmed that sortilin, encoded by SORT1, can bind with progranulin and deliver a mature secretory isoform of progranulin to lysosomes, and progranulin is then cleaved. In the present study, we aimed to figure out whether sortilin could affect the expression and cellular localization of progranulin and regulate cell apoptosis during hypoxia–ischemia. In this study, oxygen–glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons was used to mimic hypoxic–ischemic episodes. After OGD/R, the neuroprotective effects of progranulin against hypoxia–ischemia were examined, and primary cortical neurons were transduced with a SORT1 knockdown lentivirus to inhibit the expression of sortilin. The results showed that sortilin inhibition increased PGRN expression and alleviated cell injury induced by hypoxia–ischemia. Additionally, sortilin inhibition was associated with less PGRN localization in lysosomes. All of these findings suggest that sortilin can regulate the expression of PGRN, most likely by transporting it to lysosomes and affecting the cell injury in hypoxia–ischemia.

前颗粒蛋白是在神经元和小胶质细胞中表达的一种分泌的糖蛋白，参与维持生理功能。许多研究发现前颗粒蛋白可能在缺血性脑损伤中起保护作用，但对缺氧缺血后前颗粒蛋白的表达水平和细胞定位状态的调控知之甚少。研究证实，由SORT1编码的sortilin可以与颗粒蛋白原结合，并向溶酶体中释放颗粒蛋白的成熟分泌同工型，然后将颗粒蛋白裂解。在本研究中，我们旨在确定低氧缺血期间sortilin是否会影响前颗粒蛋白的表达和细胞定位以及调节细胞凋亡。在这个研究中，初级皮层神经元中的氧葡萄糖剥夺/复氧（OGD / R）用于模拟缺氧缺血性发作。OGD / R后，检查了颗粒蛋白原对缺氧缺血的神经保护作用，并用SORT1敲低慢病毒转导了原代皮层神经元以抑制sortilin的表达。结果表明，sortilin抑制可增加PGRN表达并减轻缺氧缺血引起的细胞损伤。此外，sortilin抑制与溶酶体中较少的PGRN定位有关。所有这些发现表明，sortilin可以调节PGRN的表达，很可能是通过将其转运至溶酶体并影响缺氧缺血性细胞的损伤。并用SORT1敲低慢病毒转导初级皮质神经元以抑制sortilin的表达。结果表明，sortilin抑制可增加PGRN表达并减轻缺氧缺血引起的细胞损伤。此外，sortilin抑制与溶酶体中较少的PGRN定位有关。所有这些发现表明，sortilin可以调节PGRN的表达，很可能是通过将其转运至溶酶体并影响缺氧缺血性细胞的损伤。并用SORT1敲低慢病毒转导初级皮质神经元以抑制sortilin的表达。结果表明，sortilin抑制可增加PGRN表达并减轻缺氧缺血引起的细胞损伤。此外，sortilin抑制与溶酶体中较少的PGRN定位有关。所有这些发现表明，sortilin可以调节PGRN的表达，很可能是通过将其转运至溶酶体并影响缺氧缺血细胞的损伤。