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REDUCED NACL COTRANSPORTER ABUNDANCE AND PHOSPHORYLATION IN URINARY EXTRACELLULAR VESICLES IN RESPONSE TO KCL SUPPLEMENTS IN HEALTHY ADULTS MAINTAINED ON A HIGH-NA+ LOW-K+ DIET: A

Objective: A renal-K switch mechanism has been established in rodent models and demonstrates that a low K+ intake acts as a trigger that links K+ and Na+-dependent blood pressure. This mechanism involves activation (phosphorylation) of the NaCl-cotransporter NCC in the distal convoluted tubule in response to low-K+ intake and suppression (dephosphorylation) after a high-K+ intake. As a first step to establishing a similar mechanism in humans, this study aimed to examine if the abundance of NCC and pNCC in urinary extracellular vesicles (uEVs) of healthy adults on a high-Na+ diet changes in response to alterations in K+ intake. Design and method: The study design was a double-blind, randomised and placebo-controlled trial. Healthy adults maintained on a high-Na+ (∼200mmol/day), low-K+ (∼60mmol/day) diet underwent a run-in period of 1-week followed by a cross-over study, with 5 days supplementary KCl (active phase, Span K, 24mmol thrice daily) or 5 days placebo administered in random order and separated by 2 days washout. NCC and pNCC were measured in uEVs after each phase. Participants who met dietary compliance (no less than 80%) and increased urinary K+ in the active phase were included in analyses. Results: Among the 18 (out of 28) participants who met inclusion criteria, supplementary KCl administration (versus placebo) in the active phase was associated with higher levels of plasma K+ (p < 0.001) and 24-Hour urine levels of K+ (p < 0.001), Cl- (p < 0.001) and aldosterone (p < 0.001), and lower levels of 24-Hour urinary Na+/K+ (p < 0.001), NCC (p < 0.01) and pNCC (p < 0.05); whilst the ratio of pNCC/NCC remained unchanged. Correlation analyses revealed an inverse correlation of plasma K+ with NCC (R2 = 0.11, p = 0.05) and δurinary K+ with δpNCC (R2 = 0.23, p = 0.04). Ambulatory systolic blood pressure positively correlated with timed urinary Na+/K+ (R2 = 0.08, p = 0.04) during interventions.δ Conclusions: KCl supplementation in healthy adult subjects maintained on a high-Na+ low-K+ diet was associated with a fall in NCC and pNCC, consistent with the renal-K switch mechanism, and offers a useful target for dietary intervention.