Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Theranostics. 2024 Jan 1;14(2):861-878. doi: 10.7150/thno.87317. eCollection 2024.
Vascular calcification (VC) is a life-threatening complication in patients with chronic kidney disease (CKD) caused mainly by hyperphosphatemia. However, the regulation of VC remains unclear despite extensive research. Although serum- and glucocorticoid-induced kinase 3 (SGK3) regulate the sodium-dependent phosphate cotransporters in the intestine and kidney, its effect on VC in CKD remains unknown. Additionally, type III sodium-dependent phosphate cotransporter-1 (Pit-1) plays a significant role in VC development induced by high phosphate in vascular smooth muscle cells (VSMCs). However, it remains unclear whether SGK3 regulates Pit-1 and how exactly SGK3 promotes VC in CKD via Pit-1 at the molecular level. Thus, we investigated the role of SGK3 in the certified outflow vein of arteriovenous fistulas (AVF) and aortas of uremic mice. In our study, using uremic mice, we observed a significant upregulation of SGK3 and calcium deposition in certified outflow veins of the AVF and aortas, and the increase expression of SGK3 was positively correlated with calcium deposition in uremic aortas. , the downregulation of SGK3 reversed VSMCs calcification and phenotype switching induced by high phosphate. Mechanistically, SGK3 activation enhanced the mRNA transcription of Pit-1 through NF-κB, downregulated the ubiquitin-proteasome mediated degradation of Pit-1 via inhibiting the activity of neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2), an E3 ubiquitin ligase. Moreover, under high phosphate stimulation, the enhanced phosphate uptake induced by SGK3 activation was independent of the increased protein expression of Pit-1. Our co-immunoprecipitation and kinase assays confirmed that SGK3 interacts with Pit-1 through Thr468 in loop7, leading to enhanced phosphate uptake. Thus, it is justifiable to conclude that SGK3 promotes VC in CKD by enhancing the expression and activities of Pit-1, which indicate that SGK3 could be a therapeutic target for VC in CKD.
血管钙化（VC）是慢性肾脏病（CKD）患者的一种危及生命的并发症，主要由高磷血症引起。然而，尽管进行了广泛的研究，VC 的调节仍然不清楚。尽管血清和糖皮质激素诱导激酶 3（SGK3）调节肠道和肾脏中的钠依赖性磷酸盐共转运体，但它对 CKD 中的 VC 的影响尚不清楚。此外，III 型钠依赖性磷酸盐共转运体-1（Pit-1）在高磷酸盐诱导的血管平滑肌细胞（VSMCs）中 VC 的发展中起重要作用。然而，尚不清楚 SGK3 是否调节 Pit-1，以及 SGK3 如何通过 Pit-1在分子水平上在 CKD 中促进 VC。因此，我们研究了 SGK3 在动静脉瘘（AVF）的已认证流出静脉和尿毒症小鼠的主动脉中的作用。在我们的研究中，使用尿毒症小鼠，我们观察到 SGK3 和钙在 AVF 的已认证流出静脉和主动脉中的明显上调，并且 SGK3 的增加表达与尿毒症主动脉中的钙沉积呈正相关。SGK3 的下调逆转了高磷酸盐诱导的 VSMCs 钙化和表型转换。从机制上讲，SGK3 通过 NF-κB 增强 Pit-1 的 mRNA 转录，通过抑制神经前体细胞表达发育下调蛋白 4 亚型 2（Nedd4-2）的活性，从而下调 Pit-1 的泛素-蛋白酶体介导的降解，Nedd4-2 是一种 E3 泛素连接酶。此外，在高磷酸盐刺激下，SGK3 激活诱导的磷酸盐摄取增加与 Pit-1 的蛋白表达增加无关。我们的共免疫沉淀和激酶测定证实 SGK3 通过环 7 中的 Thr468 与 Pit-1 相互作用，导致磷酸盐摄取增加。因此，可以合理地得出结论，SGK3 通过增强 Pit-1 的表达和活性来促进 CKD 中的 VC，这表明 SGK3 可能是 CKD 中 VC 的治疗靶点。
