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

Abstract

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.

Urinary extracellular vesicles carry valuable hints through mRNA for the understanding of endocrine hypertension

“…Interestingly, in those studies that investigated a specific mRNA of uEVs in endocrine hypertension, namely NCC in PA and 11β-HSD2 in AME ( 9 , 15 ), the results were somewhat different from those expected when looking at the specific protein studies. Previous data on uEVs NCC protein demonstrated that patients with PA are characterized by a higher level of NCC and pNCC in comparison to essential hypertensive patients, with a modulation by both mineralocorticoid administration and potassium levels, and a higher abundance in patients with documented monolateral versus bilateral PA disease ( 16 , 17 , 20 , 23 ). Consistent with these findings, one could expect a reflection of the differences in protein abundance in the abundance of the corresponding mRNA, but this did not occur.…”

“…Besides lipids and proteins, uEVs also carry RNA molecules and are secreted from renal epithelial cells into the urine, thus providing access to information about kidney tissue physiology and possibly to kidney-related diseases pathophysiology ( 21 , 22 ). Most studies, however, have focused, on the proteins and non-coding RNA profiles of uEVs and almost all are related to endocrine hypertension referring more specifically to primary aldosteronism (PA) and to apparent mineralocorticoid excess (AME) ( 12 – 14 , 16 , 17 , 19 , 20 , 23 , 24 ).…”

Diabetes with kidney injury may change the abundance and cargo of urinary extracellular vesicles

“…Therefore, the uEV-to-UCr ratio may be considered as a housekeeper indicating the stage of DN. uEVs may be non-invasive biomarkers in predicting and monitoring the progression of renal physiological and pathological conditions (38,39). More and more evidence have established a valuable role of uEVs in renal physiology and pathology (38,(40)(41)(42).…”

“…Therefore, the uEV-to-UCr ratio may be considered as a housekeeper indicating the stage of DN. uEVs may be non-invasive biomarkers in predicting and monitoring the progression of renal physiological and pathological conditions ( 38 , 39 ).…”

Extracellular Vesicles in Kidney Disease

“…EVs feature in renal physiology and are widely involved in the occurrence and progression of various kidney diseases. It can be used for the diagnosis of kidney diseases and be instrumental in the treatment of renal diseases [10,11].…”