Using human urinary extracellular vesicles to study physiological and pathophysiological states and regulation of the sodium chloride cotransporter

The thiazide-sensitive sodium chloride cotransporter (NCC), expressed in the renal distal convoluted tubule, plays a major role in Na+, Cl- and K+ homeostasis and blood pressure as exemplified by the symptoms of patients with non-functional NCC and Gitelman syndrome. NCC activity is modulated by a variety of hormones, but is also influenced by the extracellular K+ concentration. The putative renal-K+ switch mechanism is a relatively cohesive model that links dietary K+ intake to NCC activity, and may offer new targets for blood pressure control. However, a remaining hurdle for full acceptance of this model is the lack of human data to confirm molecular findings from animal models. Extracellular vesicles (EVs) have attracted attention from the scientific community due to their potential roles in intercellular communication, disease pathogenesis, drug delivery and as possible reservoirs of biomarkers. Urinary EVs (uEVs) are an excellent sample source for the study of physiology and pathology of renal, urothelial and prostate tissues, but the diverse origins of uEVs and their dynamic molecular composition present both methodological and data interpretation challenges. This review provides a brief overview of the state-of-the-art, challenges and knowledge gaps in current uEV-based analyses, with a focus on the application of uEVs to study the renal-K+ switch and NCC regulation. We also provide recommendations regarding biospecimen handling, processing and reporting requirements to improve experimental reproducibility and interoperability towards the realisation of the potential of uEV-derived biomarkers in hypertension and clinical practice.

Automated summary

The thiazide-sensitive sodium chloride cotransporter (NCC) plays a major role in electrolyte balance and blood pressure regulation. The renal-K+ switch mechanism, which links dietary potassium intake to NCC activity, may offer new targets for blood pressure control. However, the lack of human data to confirm findings from animal models is a hurdle for full acceptance of this model. Urinary extracellular vesicles (uEVs) have potential as biomarkers for studying renal physiology and pathology. Challenges include the diverse origins and dynamic molecular composition of uEVs.