Abstract
Distal sodium transport is a final step in the regulation of blood pressure. As such, understanding how the two main sodium transport proteins, the thiazide-sensitive sodium chloride cotransporter (NCC) and the epithelial sodium channel (ENaC), are regulated is paramount. Both are expressed in the late distal nephron; however, no evidence has suggested that these two sodium transport proteins interact. Recently, we established that these two sodium transport proteins functionally interact in the second part of the distal nephron (DCT2). Given their co-localization within the DCT2, we hypothesized that NCC and ENaC interactions might be modulated by aldosterone (Aldo). Aldo treatment increased NCC and αENaC colocalization (electron microscopy) and interaction (coimmunoprecipitation). Finally, with co-expression of the Aldo-induced protein serum- and glucocorticoid-inducible kinase 1 (SGK1), NCC and αENaC interactions were increased. These data demonstrate that Aldo promotes increased interaction of NCC and ENaC, within the DCT2 revealing a novel method of regulation for distal sodium reabsorption.
Highlights
The ASDN is comprised of the late distal convoluted tubule (DCT2), connecting tubule (CNT) and cortical collecting duct (CCD)
Given the importance of Aldo in regulating both NCC and ENaC, we hypothesized that Aldo would modulate their interactions in the DCT2
Apical images were obtained from the DCT2, the only portion of the nephron containing both NCC and ENaC
Summary
The ASDN is comprised of the late distal convoluted tubule (DCT2), connecting tubule (CNT) and cortical collecting duct (CCD). NCC is expressed fully along the DCT, while ENaC expression begins at the DCT2 and continues throughout the remainder of the ASDN. Studies have demonstrated that NCC and ENaC are co-expressed in one segment of the ASDN, the DCT25–12. No studies have suggested any interaction between these two transport proteins. Utilizing a mammalian two-hybrid system we demonstrated a direct interaction between these proteins[12]. Inhibition of NCC function with thiazides reduced ENaC open probability, confirming a functional interaction of these proteins[12]. Mechanisms that might regulate this interaction are unknown. Given their location in the ASDN, we hypothesized that aldosterone might modulate their interactions. We report that this hypothesis is true; the interaction of these two key Na+ transport proteins is regulated by aldosterone
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