Dept. of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States.
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States.
Biochem Pharmacol. 2019 Nov;169:113644. doi: 10.1016/j.bcp.2019.113644. Epub 2019 Sep 19.
A hallmark of acute kidney injury (AKI) is vascular rarefication and mitochondrial dysfunction. Promoting vascular recovery following AKI could facilitate kidney repair as the vasculature is responsible for oxygen and nutrient delivery to extravascular tissues. Little is known about mitochondrial biogenesis (MB) in endothelial cells, and the role of 5-HT receptor signaling in MB has only been studied in epithelial cells. Our laboratory has shown that stimulating MB through the 5-HT receptor promotes recovery from AKI and that 5-HT receptor knockout mice have decreased MB and poor renal recovery. We hypothesized that the 5-HT receptor plays a role in vascular homeostasis and mediates MB in renal endothelial cells. 5-HT receptor knockout mice had decreased renal vascular content, as evidenced by decreased CD31 endothelial cells and αSMA vessels. Human glomerular endothelial cells (HEC) and mouse glomerular endothelial cells (MEC) expressed the 5-HT receptor. Treatment of HEC and MEC with 5-HT receptor agonists LY344864 or lasmiditan (0-500 nM) induced MB as evidenced by maximal mitochondrial respiration, a marker of MB. HEC and MEC treated with lasmiditan or LY344864 also had increased nuclear- and mitochondrial-encoded proteins (PGC1α, COX-1, and VDAC), and mitochondrial number, confirming MB. Treatment of HEC with LY344864 or lasmiditan enhanced endothelial branching morphogenesis and migration, indicating a role for 5-HT receptor stimulation in angiogenic pathways. We propose that stimulation of 5-HT receptor is involved in MB in endothelial cells and that treatment with 5-HT receptor agonists could restore stimulate repair and recovery following kidney injury.
急性肾损伤 (AKI) 的一个标志是血管稀疏和线粒体功能障碍。促进 AKI 后的血管恢复可以促进肾脏修复，因为血管负责向血管外组织输送氧气和营养。内皮细胞中线粒体生物发生 (MB) 的知之甚少，5-HT 受体信号在 MB 中的作用仅在上皮细胞中进行了研究。我们的实验室表明，通过 5-HT 受体刺激 MB 可促进 AKI 的恢复，并且 5-HT 受体敲除小鼠的 MB 减少且肾脏恢复不良。我们假设 5-HT 受体在血管稳态中发挥作用，并介导肾脏内皮细胞中的 MB。5-HT 受体敲除小鼠的肾脏血管含量减少，这表现在 CD31 内皮细胞和αSMA 血管减少。人肾小球内皮细胞 (HEC) 和鼠肾小球内皮细胞 (MEC) 表达 5-HT 受体。用 5-HT 受体激动剂 LY344864 或 lasmiditan（0-500 nM）处理 HEC 和 MEC 可诱导 MB，这表现为最大的线粒体呼吸，这是 MB 的标志物。用 lasmiditan 或 LY344864 处理的 HEC 和 MEC 还增加了核编码和线粒体编码蛋白（PGC1α、COX-1 和 VDAC）和线粒体数量，证实了 MB。用 LY344864 或 lasmiditan 处理 HEC 可增强内皮细胞的分支形态发生和迁移，表明 5-HT 受体刺激在血管生成途径中发挥作用。我们提出，刺激 5-HT 受体参与内皮细胞中的 MB，并且用 5-HT 受体激动剂治疗可能会恢复刺激损伤后肾脏的修复和恢复。
