Enhanced activity of the renal Na+K+2Cl– transporter, NKCC2, has been linked to hypertension, but the mechanisms that regulate NKCC2 activity are largely unknown. New research now reports a role for Alström syndrome protein 1 (ALMS1) in mediating NKCC2 trafficking and activity. “Our study shows that ALMS1 dysfunction causes hypertension, decreases renal sodium excretion and increases NKCC2-mediated NaCl transport in the thick ascending limb (TAL),” explains Pablo Ortiz.

The carboxyl terminus of NKCC2 is important for its trafficking to and from the membrane. Using a targeted proteomics approach, Ortiz and colleagues identified ALMS1 as a protein that interacts with this region of NKCC2 and with other proteins involved in endocytosis, suggesting a role for ALMS1 in NKCC2 trafficking. To assess the functional relevance of AMLS1, the researchers generated ALMS1-knockout rats. These rats appeared largely normal by 12 weeks of age, but were hypertensive and exhibited increased sensitivity to high salt intake. Knockout rats were more sensitive to the diuretic and natriuretic effects of the NKCC2 inhibitor bumetanide and had an impaired ability to respond to acute volume loading. Together these data showed that ALMS1-knockout rats exhibited higher NaCl reabsorption in the TAL than wild-type rats.

Finally, the researchers used a cell-surface biotinylation assay to show that deletion or silencing of ALMS1 decreased NKCC2 endocytosis, causing it to accumulate at the cell surface. “These findings explain how defective ALMS1 induces NKCC2-mediated NaCl transport in the TAL, and provides an explanation for some of the syndromic characteristics of Alström syndrome, which is caused by loss-of-function mutations in ALMS1,” says Ortiz. “Moreover, single-nucleotide polymorphisms in ALMS1 are associated with renal dysfunction, obesity and metabolic syndrome. It would be interesting to now look at whether this gene is associated with hypertension in the general population.”