Despite the strong links between high dietary salt intake and disease, surprisingly little is known about the regulation of human salt taste in health and disease. Several diseases, including chronic kidney disease (CKD), are characterized by impaired salt taste and therefore result in an undesirable high dietary salt intake. Human salt taste is mediated by the epithelial sodium channel (ENaC), but its regulation in taste buds is poorly understood. From its regulation in the kidney, it is known that ENaC can be activated by proteolytic cleavage. Recently it was shown that the salivary proteome of salt-sensitive subjects is enriched with proteases, whereas salt-resistant subjects had more protease inhibitors.

We assessed the salt detection threshold (SDT), the lowest detectable concentration, in CKD patients and controls, collected saliva and analysed the salivary content. Our results confirmed that on average CKD patients have a higher SDT than controls. Similarly, higher age correlates with higher SDT. Next, we aim to explore the relationship between salt taste sensitivity and salivary content, e.g. electrolytes and proteome, and to identify any differences related to kidney disease. The saliva of the patients showed increased mean pH, osmolality, and [Cl-], and reduced [Ca2+]. Analysis of the proteomes is currently ongoing.

In a subsequent phase, we will analyse whether proteins whose abundance in salivary proteomes correlates with salt sensitivity contribute to ENaC activity. Based on knowledge of regulation of ENaC activity, we will first focus on proteases and protease inhibitors. For these analyses we have created two human ENaC expressing models, Xenopus oocytes and Caenorhabditis elegans. We will incubate these models with proteins enriched in saliva and measure regulation of ENaC by measuring currents or behaviour, respectively. We expect that our analyses will provide a new paradigm for human salt taste with possibilities for intervention.