Lipid Profiles of Urinary Extracellular Vesicles Released during the Inactive and Active Phases of Aged Male Mice with Spontaneous Hypertension

Abstract

Hypertension remains a major problem, especially in the elderly, as it increases the risk for cardiovascular, coronary artery, cerebrovascular, and kidney diseases. Extracellular vesicles (EVs) play a role in the aging process and contribute to pathophysiology. Our goal was to examine differences in lipid profiles of urinary EVs (uEVs) collected during the inactive and active phases of aged mice and investigate whether these EVs regulate the density of lipid rafts in mouse cortical collecting duct (mpkCCD) principal cells. Here, we demonstrate the epithelial sodium channel (ENaC) inhibitor benzyl amiloride reduced systolic blood pressure in aged male mice during the inactive and active phases. Lipidomics data demonstrate differential enrichment of lipids between the two groups. For example, there are more phosphatidylethanolamine plasmalogens, particularly in the form of alkyl phosphatidylethanolamines, that are enriched in active phase uEVs compared to inactive phase uEVs from the same mice. Amiloride-sensitive transepithelial current increased more in mpkCCD cells challenged with uEVs from the active phase group. Moreover, more ENaC alpha protein was distributed to lipid raft fractions of mpkCCD cells challenged with active phase uEVs. Taken together, the identification of bioactive lipids associated with lipid rafts that are enriched in EVs released during the active phase of aged mice may offer clues to help understand lipid raft organization in recipient principal cells after EV uptake and increased renal ENaC activity, leading to a time-of-day dependent regulation of blood pressure in an aging model.

Extracellular vesicles as carriers of mRNA: Opportunities and challenges in diagnosis and treatment

“…Recent work highlighted the role of the circadian rhythm in EV production and function. In humans and rodents, the concentration of circulating EVs increases during the active phase and decreases over inactive phase [101][102][103][104]. In mice, this was found to be inversely related to corticosterone levels [102].…”

Extracellular vesicles: A new frontier in the theranostics of cardiovascular diseases

“…Lipidomic profiling of EVs offers a comprehensive view of the lipid composition, reflective of cellular conditions in the cardiovascular environment. These lipid signatures, including bioactive lipid mediators, shed light on lipid metabolism dysregulation, a hallmark of hypertension [34,35]. Furthermore, characterizing the surface proteome of EVs allows the identification of disease-specific markers of malaria and hyperlipoidemia, facilitating the development of highly selective diagnostic tools [23,36].…”

Extracellular Vesicles: Investigating the Pathophysiology of Diabetes-Associated Hypertension and Diabetic Nephropathy

“…A study by Lugo et al showed differences in the amount of annexin A2, GAPDH, TSG101, and caveolin-1 proteins, as well as lipids including specific hexosylceramides, monoacylglycerols, phosphatidylcholines, lysophosphatidylethanolamine, phosphatidylethanolamine, and phosphatidylglycerol enriched in uEVs from male and female diabetic db/db mice treated with human AAT (hAAT) or the vehicle [ 42 ]. A study by Lopez et al showed differences in the amounts of syntein and flotillin proteins, as well as lipids including specific phosphatidylethanolamines, triacylglycerols, and phosphatidylcholines enriched in uEVs from aged male mice with spontaneous hypertension [ 15 ]. Yeung et al performed a functional enrichment analysis of circadian proteins and showed actin-binding and intermediate filament proteins associated with the cytoskeleton had peak abundances in small EVs that were temporally separated at 8 h and ~23 h after synchronization [ 76 ].…”

“…In addition, EVs are used in multiple applications [ 12 , 13 , 14 ]. EVs isolated from biological fluids including urine [ 15 ], plasma [ 16 ], and cerebrospinal fluid [ 17 ] represent a rich source of biomarkers. Additionally, the profiling of the EV cargo can be used as markers of diagnosis and prognosis [ 18 , 19 ].…”