Huang Mingcong, Chang Jing, Liu Yu, Yin Jiming, Zeng Xiangjun
School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Department of Physiology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
Peptides. 2025 Jan;183:171333. doi: 10.1016/j.peptides.2024.171333. Epub 2024 Dec 5.
Renal hemodynamics damage, an important driving mechanism of diabetic nephropathy (DN), is related to many abnormal endothelial released molecules, such as endothelial nitrogen monoxide synthase (eNOS) and endothelin-1 (ET-1), caused by glomerular endothelial cells dysfunction. Apelin, as the endogenous ligand for APJ, was reported to be associated with endothelial cell dysfunction in diabetes. Therefore, it is hypothesized that apelin/APJ increased renal perfusion in DN through regulating endothelial released molecules. Diabetic models were replicated via injecting STZ intraperitoneally (40 mg/kg/day) for 5 consecutive days. Apelin-13 was infused with micro-osmotic pump at 30 μg/kg/day for 4 weeks. The results showed that apelin increased renal blood flow by increasing phosphorylated eNOS and decreasing ET-1 in diabetic mice, which were cancelled in endothelial-specific APJ knockout mice or whole-body large conductance Ca-activated K (BKCa) channel knockout rats. Additionally, apelin/APJ activated BKCa channel via increasing expression of BKCa subunits through PI3K/AKT/GSK-3β/Nrf2 pathway but not increasing intracellular Ca concentration under high glucose conditions. In conclusion, this study revealed that apelin/APJ increased renal blood flow in early phase of DN via increasing p-eNOS and decreasing ET-1 in glomerular endothelial cells dependent on PI3K/AKT/GSK-3β/Nrf2 pathway induced expression of BKCa subunits.
肾血流动力学损伤是糖尿病肾病（DN）的重要驱动机制，与许多由肾小球内皮细胞功能障碍引起的内皮释放分子异常有关，如内皮型一氧化氮合酶（eNOS）和内皮素-1（ET-1）。Apelin作为APJ的内源性配体，据报道与糖尿病中的内皮细胞功能障碍有关。因此，推测Apelin/APJ通过调节内皮释放分子增加DN中的肾灌注。通过连续5天腹腔注射链脲佐菌素（STZ，40mg/kg/天）复制糖尿病模型。以30μg/kg/天的剂量用微渗透泵输注Apelin-13，持续4周。结果表明，Apelin通过增加糖尿病小鼠的磷酸化eNOS和降低ET-1来增加肾血流量，而在内皮特异性APJ基因敲除小鼠或全身大电导钙激活钾（BKCa）通道基因敲除大鼠中，这种作用被消除。此外，在高糖条件下，Apelin/APJ通过PI3K/AKT/GSK-3β/Nrf2途径增加BKCa亚基的表达来激活BKCa通道，而不是增加细胞内钙浓度。总之，本研究表明，Apelin/APJ在DN早期通过增加肾小球内皮细胞中的p-eNOS和降低ET-1来增加肾血流量，这依赖于PI3K/AKT/GSK-3β/Nrf2途径诱导的BKCa亚基表达。
