Adult mouse kidney stem cell‐derived exosomes attenuate blood pressure and improve kidney functions in aged mice

Abstract

The physiological function of stem cell-derived extracellular vesicles remains elusive. Most recently, we isolated kidney stem cells (KSC) from adult mouse kidneys and studied the role of KSC-derived exosomes in blood pressure regulation in hypertensive aged mice. We treated aged mice with KSC-exosome (~1.26×1011 ± 1.94×109 particles/mouse/day) or PBS by intraperitoneal injection for 5 days. We found that the blood pressure was reduced (from 150.8±12.2 to 128.6±3 mmHg) at day 6 in KSC-exosome-treated aged mice, while the blood pressure remained unchanged in PBS-treated aged mice. Blood pressure continued to decrease to 116±8.2 mmHg at day 14 after KSC-exosome treatment. Hypertension reemerged gradually and relapsed at day 28 after treatment. To assess the kidney functions, we collected 6-hour urine at day 5 of the treatment. KSC-exosome treatment significantly reduced the increases in urine albumin and creatinine in aged mice, indicating that KSC-exosomes improve aging-associated kidney dysfunction. Notably, the glomerular filtration rate (GFR) was significantly increased in KSC-exosome-treated aged mice, suggesting improved glomerular function. Urinary cytokine levels were increased in aged mice which were largely reduced by KSC-exosomes. KSC-exosomes effectively reduced the kidney injury markers TIM1 and adiponectin and inflammation marker NGAL which were confirmed by ELISA. These data suggest that KSC-exosome treatment attenuates aging-associated renal inflammation and kidney injury. To explore the mechanisms by which KSC-exosome attenuates blood pressure and improves kidney functions in aged mice, we performed proteome analysis of KSC-exosomes by mass spectrometry. We found several pathways that involve in the kidney development were upregulated in KSC-exosome compared to renal tubule cells (RTC) derived-exosomes. Interestingly, KSC-exosome induced cell proliferation and cell migration after injury possibly through activation of AKT signaling demonstrated in vitro. In conclusion, our finding provided the first evidence that the adult mouse kidney stem cell-derived exosomes attenuate aging-associated hypertension and kidney dysfunctions. KSC-exosome treatment may be a novel therapeutic strategy for hypertension-associated kidney injuries in aging.