Taguchi Kumiko, Furukawa Tomoya, Matsumoto Takayuki, Kobayashi Tsuneo
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Second Department of Pharmacology, School of Pharmaceutical Sciences, Kyushu University of Medical Science, 1714-1 Yoshino-cho, Nobeoka, Miyazaki 882-8508, Japan.
Biol Pharm Bull. 2025;48(4):422-431. doi: 10.1248/bpb.b25-00009.
Mineralocorticoid receptor (MR) blockers reduce cardiovascular complications as MRs play a crucial role in cardiovascular regulation. Diabetic cardiovascular complications are caused by vascular endothelial dysfunction. This study used a type 2 diabetic mouse model (DM) to investigate whether esaxerenone (ESAX), an MR blocker, ameliorates vascular endothelial dysfunction. ESAX (3 mg/kg/d) was administered via diet to KK-Ay mice or C57BL/6J mice, a nondiabetic control (Control), for 8 weeks, and metabolic parameters and blood pressure were measured. Vascular responses of the aortic segments were analyzed with acetylcholine, sodium nitroprusside, UK14304, or phenylephrine (PE). The other aortas were used for Western blot analysis. DM mice exhibited higher plasma glucose, insulin, metabolic parameters, and blood pressure levels than those of the Control mice. Parameters that did not include blood pressure were unaltered by DM or ESAX-administered DM (DM + ESAX). However, DM impaired UK14304-induced endothelial-dependent relaxation and nitric oxide production and elevated PE-induced contraction. ESAX administration ameliorated endothelial dysfunction and improved the protein kinase B (Akt) phosphorylation under α-agonist UK14304 stimulation in the aorta from DM mice compared with that of the Control mice. However, ESAX did not recover the increased G protein-coupled receptor kinase 2 (GRK2) expression and activity in the DM aorta. Furthermore, the DM-induced phosphorylation of serum and glucocorticoid-regulated kinase 1 (SGK1) was inhibited by ESAX. Overall, ESAX attenuates the development of DM-induced endothelial dysfunction by reducing SGK1 activity and enhancing Akt activity without affecting the GRK2 pathway. These results suggest that the vascular protective effects of ESAX could be employed for diabetic vascular complications.
盐皮质激素受体（MR）阻滞剂可降低心血管并发症，因为MR在心血管调节中起关键作用。糖尿病心血管并发症是由血管内皮功能障碍引起的。本研究使用2型糖尿病小鼠模型（DM）来研究MR阻滞剂依普利酮（ESAX）是否能改善血管内皮功能障碍。将ESAX（3毫克/千克/天）通过饮食给予KK-Ay小鼠或非糖尿病对照（对照）C57BL/6J小鼠，持续8周，并测量代谢参数和血压。用乙酰胆碱、硝普钠、UK14304或去氧肾上腺素（PE）分析主动脉段的血管反应。将其他主动脉用于蛋白质印迹分析。与对照小鼠相比，DM小鼠的血糖、胰岛素、代谢参数和血压水平更高。DM或给予ESAX的DM（DM + ESAX）对不包括血压在内的参数没有影响。然而，DM损害了UK14304诱导的内皮依赖性舒张和一氧化氮生成，并提高了PE诱导的收缩。与对照小鼠相比，给予ESAX改善了DM小鼠主动脉在α-激动剂UK14304刺激下的内皮功能障碍，并改善了蛋白激酶B（Akt）的磷酸化。然而，ESAX并未恢复DM主动脉中增加的G蛋白偶联受体激酶2（GRK2）的表达和活性。此外，ESAX抑制了DM诱导的血清和糖皮质激素调节激酶1（SGK1）的磷酸化。总体而言，ESAX通过降低SGK1活性和增强Akt活性来减轻DM诱导的内皮功能障碍的发展，而不影响GRK2途径。这些结果表明，ESAX的血管保护作用可用于糖尿病血管并发症。
