Lasmiditan induces mitochondrial biogenesis in primary mouse renal peritubular endothelial cells and augments wound healing and tubular network formation.

IF 5 2区 生物学 Q2 CELL BIOLOGY
Austin D Thompson, Kai W McAlister, Natalie E Scholpa, Jaroslav Janda, John Hortareas, Rick G Schnellmann
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引用次数: 0

Abstract

Kidney disease (KD) is a progressive and life-threatening illness that has manifested into a global health crisis, impacting >10% of the general population. Hallmarks of KD include tubular interstitial fibrosis, renal tubular cell atrophy/necrosis, glomerulosclerosis, persistent inflammation, microvascular endothelial cell (MV-EC) dysfunction/rarefaction, and mitochondrial dysfunction. Following acute kidney injury (AKI), and/or during KD onset/progression, MV-ECs of the renal peritubular endothelial capillaries (RPECs) are highly susceptible to injury, dysfunction, and rarefaction. Pharmacological induction of mitochondrial biogenesis (MB) via 5-hydroxytryptamine receptor 1F (HTR1F) agonism has been shown to enhance mitochondrial function and renal vascular recovery post-AKI in mice; however, little is known about MB in relation to renal MV-ECs and RPEC repair mechanisms. To address this gap in knowledge, the in vitro effects of the potent and selective FDA-approved HTR1F agonist lasmiditan were tested on primary mouse renal peritubular endothelial cells (MRPECs). Lasmiditan increased mitochondrial maximal respiration rates, mRNA and protein expression of MB-related genes, and mitochondrial number in MRPECs. MRPECs were then exposed to pro-inflammatory agents associated with renal MV-EC dysfunction, AKI, and KD (i.e., lipopolysaccharides, transforming growth factor-β1, and tumor necrosis factor-α), in the presence/absence of lasmiditan. Lasmiditan treatment augmented MRPEC wound healing, endothelial tubular network formation (ETNF), enhanced barrier integrity, and blunted inflammatory-induced MV-EC dysfunctions. Together, these data suggest that lasmiditan induces MB and improves wound healing and ETNF of primary MRPECs in the presence/absence of pro-inflammatory agents, highlighting a potential therapeutic role for lasmiditan treatment in renal MV-EC dysfunction, AKI, and/or KD.NEW & NOTEWORTHY Lasmiditan, an FDA-approved HTR1F agonist, induces mitochondrial biogenesis (MB) and enhances recovery following acute kidney injury in mice. Renal microvascular endothelial cells (MV-ECs) are highly susceptible to dysfunction/rarefaction postinjury. The effect of MB on MV-EC repair/recovery is unknown. We show that lasmiditan induces MB in primary mouse renal peritubular endothelial cells and improves wound healing, endothelial tubular network formation, and barrier integrity after inflammatory-induced dysfunction, indicative of its potential for the treatment of kidney diseases.

拉斯米坦诱导原代小鼠肾小管周围内皮细胞线粒体生物发生,促进伤口愈合和小管网络形成。
肾脏疾病(KD)是一种进行性和危及生命的疾病,已表现为全球健康危机,影响全球约10%的人口。KD的特征包括小管间质纤维化、肾小管细胞萎缩/坏死、肾小球硬化、持续炎症、微血管内皮细胞(pv - ec)功能障碍/稀薄和线粒体功能障碍。急性肾损伤(AKI)后,和/或KD发作/进展期间,肾小管周围内皮毛细血管(RPECs)的mv - ec极易受到损伤、功能障碍和稀薄的影响。通过5-羟色胺受体1F (HTR1F)激动作用诱导线粒体生物发生(MB)已被证明可增强小鼠aki后线粒体功能和肾血管恢复;然而,MB与肾MV-ECs和RPECs修复机制的关系尚不清楚。为了解决这一知识空白,fda批准的强效和选择性HTR1F激动剂lasmiditan在原代小鼠肾小管周围内皮细胞(mrpec)上的体外作用进行了测试。拉斯米坦增加线粒体最大呼吸速率、mb相关基因mRNA和蛋白表达以及mrpec中线粒体数量。然后将mrpec暴露于与肾MV-EC功能障碍,AKI和KD相关的促炎剂(即脂多糖,转化生长因子-β1和肿瘤坏死因子-α),存在/不存在拉西米坦。拉斯米坦治疗增强MRPECs伤口愈合,内皮管网络形成(ETNF),增强屏障完整性,钝化炎症诱导的MV-EC功能障碍。总之,这些数据表明,在存在/不存在促炎剂的情况下,拉斯米坦诱导MB,改善伤口愈合和原发性mrpec的ETNF,突出了拉斯米坦治疗肾MV-EC功能障碍、AKI和/或KD的潜在治疗作用。
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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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