Abstract
Ageing is characterized by progressive multi-organ functional decline and disrupted homeostasis adaptation. Hypertension and kidney damage become increasingly prevalent as individuals age. Given its high metabolic activity and constant exposure to reactive oxygen species, the kidney is particularly susceptible to age-related deterioration. In our study, aged mice exhibited a notable decline in glomerular filtration rate (GFR) and urinary excretion of sodium, potassium, and calcium, alongside elevated urinary creatinine levels, indicating impaired renal function associated with ageing. Histologically, aged kidneys showed glomerular collapse, thickening of the glomerular basement membrane, and increased glomerular sclerosis. Cellular senescence plays a critical role in renal ageing. Senescent cells display an array of changes in gene and protein expression and thus also altered the contents packaged into extracellular vesicles (EVs), secreted into the extracellular milieu. The protein and RNA composition of EVs varied depending on the age and pathological status of the originating parent cells. Our data showed an increased expression of EV biogenesis protein HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in aged DCT cells (aDCTs). Consistently, with an increase in EV secretion in aDCTs. Administration of young DCT (yDCT)-derived EVs into aged kidneys resulted in a significant improvement of GFR and urinary ion excretion, accompanied by a reduction in age-associated elevation of systolic blood pressure (SBP). Conversely, when administering aDCT-derived EVs to young mice, we saw a significant decrease in GFR and an increase in SBP, indicating a detrimental effect of aDCT-EVs. Proteomic analysis revealed distinct protein expression profiles between yDCT-EVs and aDCT-EVs. These differentially expressed proteins are highly enriched in ageing regulatory pathways, underscoring the crucial role of DCT-EVs in kidney rejuvenation. Intriguingly, we identified a subset of proteins exclusively present in either yDCT-EVs or aDCT-EVs. Our future research will focus on identifying the key components of DCT-EVs responsible for driving kidney rejuvenation.
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