Abstract
Renal cells of the thick ascending limb (TAL) reabsorb NaCl via the apical Na+/K+/2Cl− co-transporter NKCC2. Trafficking of NKCC2 to the apical surface regulates NKCC2-mediated NaCl absorption and blood pressure. The molecular mechanisms by which NKCC2 reaches the apical surface and their role in renal function and maintenance of blood pressure are poorly characterized. Here we report that NKCC2 interacts with the vesicle fusion protein VAMP3, and they co-localize at the TAL apical surface. We observed that silencing VAMP3 in vivo blocks constitutive NKCC2 exocytic delivery, decreasing the amount of NKCC2 at the TAL apical surface. VAMP3 is not required for cAMP-stimulated NKCC2 exocytic delivery. Additionally, genetic deletion of VAMP3 in mice decreased total expression of NKCC2 in the TAL and lowered blood pressure. Consistent with these results, urinary excretion of water and electrolytes was higher in VAMP3 knock-out mice, which produced more diluted urine. We conclude that VAMP3 interacts with NKCC2 and mediates its constitutive exocytic delivery to the apical surface. Additionally, VAMP3 is required for normal NKCC2 expression, renal function, and blood pressure.
Highlights
In the kidney, NaCl reabsorption by the thick ascending limb (TAL)2 of the loop of Henle is fundamental for concentrating the urine and control of blood pressure
We recently showed that the vesicle-associated membrane protein 2 (VAMP2), of the SNARE family of membrane fusion proteins, mediates a pathway for NKCC2 exocytic delivery that is stimulated by cAMP [3]
We recently showed that the related isoform VAMP2 co-localizes with NKCC2 at the apical membrane of TALs [3]
Summary
Genetic deletion of VAMP3 in mice decreased total expression of NKCC2 in the TAL and lowered blood pressure. Stitutive exocytic delivery [2, 3], endocytic retrieval, and recycling (4 – 6) in the absence of any stimulation, maintaining steady-state surface NKCC2 expression at a baseline level. This process of NKCC2 trafficking is a critical determinant of the absorptive capability of the TAL [7,8,9]. We recently showed that the vesicle-associated membrane protein 2 (VAMP2), of the SNARE family of membrane fusion proteins, mediates a pathway for NKCC2 exocytic delivery that is stimulated by cAMP [3]. VAMP3 contributes to steady-state surface NKCC2 expression under physiological conditions and maintains renal NaCl absorption and blood pressure homeostasis
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