Abstract
Obesity increases the risk of other diseases, including kidney disease. Local renal tubular renin-angiotensin system (RAS) activation may play a role in obesity-associated kidney disease. Extracellular vehicles (EVs) transmit necessary information in obesity and cause remote organ damage, but the mechanism is unclear. The aim of the study was to investigate whether the plasma EVs cargo miR-6869-5p causes RAS activation and renal tubular damage. We isolated plasma EVs from obese and lean subjects and analyzed differentially-expressed miRNAs using RNA-seq. Then, EVs were co-cultured with human proximal renal tubular epithelial cells (PTECs) in vitro. Immunohistochemical pathology was used to assess the degree of RAS activation and tubule injury in vivo. The tubule damage-associated protein and RAS activation components were detected by Western blot. Obesity led to renal tubule injury and RAS activation in humans and mice. Obese-EVs induce RAS activation and renal tubular injury in PTECs. Importantly, miR-6869-5p-treated PTECs caused RAS activation and renal tubular injury, similar to Obese-EVs. Inhibiting miR-6869-5p decreased RAS activation and renal tubular damage. Our findings indicate that plasma Obese-EVs induce renal tubule injury and RAS activation via miR-6869-5p transport. Thus, miR-6869-5p in plasma Obese-EVs could be a therapeutic target for local RAS activation in obesity-associated kidney disease.
Highlights
Obesity is a worldwide disease that increases the risk of other diseases and health problems [1]
For the systemic renin-angiotensin system (RAS), we observed that plasma renin, angiotensin I, and angiotensin II were significantly increased in obese subjects (p < 0.05)
These results were consistent with plasma RAS levels and indicated the occurrence of local RAS activation and renal tubule injury in obese individuals
Summary
Obesity is a worldwide disease that increases the risk of other diseases and health problems [1]. Abnormal fat deposition causes various metabolic abnormalities, including dyslipidemia, insulin resistance, atherosclerosis, and hypertension [2]. Renal lipid accumulation and lipotoxicity contribute to kidney cell injury and death, and eventually kidney disease [3]. Previous reports indicate that renal tubular changes, including hypertrophy [4] and vacuolar degeneration [5], can be seen in subjects with obesity-related kidney disease. Other studies have reported that extracellular vesicle (EV) secretion in obesity plays an essential role in kidney diseases [6, 7]. We previously described the involvement of EVs in the pathophysiology of glomerular diseases [8]
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