Renal intercalated cells are rather energized by a proton than a sodium pump

Abstract

The Na + concentration of the intracellular milieu is very low compared with the extracellular medium. Transport of Na + along this gradient is used to fuel secondary transport of many solutes, and thus plays a major role for most cell functions including the control of cell volume and resting membrane potential. Because of a continuous leak, Na + has to be permanently removed from the intracellular milieu, a process that is thought to be exclusively mediated by the Na + /K + -ATPase in animal cells. Here, we show that intercalated cells of the mouse kidney are an exception to this general rule. By an approach combining two-photon imaging of isolated renal tubules, physiological studies, and genetically engineered animals, we demonstrate that inhibition of the H + vacuolar-type ATPase (V-ATPase) caused drastic cell swelling and depolarization, and also inhibited the NaCl absorption pathway that we recently discovered in intercalated cells. In contrast, pharmacological blockade of the Na + /K + -ATPase had no effects. Basolateral NaCl exit from β-intercalated cells was independent of the Na + /K + -ATPase but critically relied on the presence of the basolateral ion transporter anion exchanger 4. We conclude that not all animal cells critically rely on the sodium pump as the unique bioenergizer, but can be replaced by the H + V-ATPase in renal intercalated cells. This concept is likely to apply to other animal cell types characterized by plasma membrane expression of the H + V-ATPase.

Water Deprivation Increases (Pro)renin Receptor Levels in the Kidney and Decreases Plasma Concentrations of Soluble (Pro)renin Receptor

“…Another possible action of increased f(P)RR in the kidney under dehydration may be mediated by the association with v-ATPase, which plays an essential role in the secretion of H + into urine in the type A intercalated cells of the collecting duct (Roy et al 2015). It is now evident that intercalated cells have regulatory roles in the salt and water reabsorption by a mechanism involving v-ATPase (Chambrey et al 2013;Roy et al 2015). It should be noted, however, that the cleavage of f(P)RR by furin may be dispensable for the biogenesis of active v-ATPase (Kinouchi et al 2013).…”

Acid-Base Homeostasis

“…Increased Na 1 reabsorption, such as with increased mineralocorticoids, will, therefore, be accompanied by increased H 1 secretion. Interestingly, the cell voltages of ICs are strikingly different from most cells, including principal cells: first, although there is little data, the cell-negative voltages as shown in Figure 4 are much less (less negative), and second, the cells are energized by the H 1 pump rather than by Na-K-ATPase as in most cells (54,57,58). H 1 secretion, including in the medullary collecting tubule, is also directly stimulated by mineralocorticoids, not just by secondary electrical effects (59,60).…”

Collecting Duct Intercalated Cell Function and Regulation

“…Type B intercalated cells have recently come to prominence with the discovery that the Na 1 -driven chloride/ bicarbonate exchanger (NDCBE) (107) and pendrin colocalize at the apical membrane of these cells ( Figure 6). Together these two transport proteins mediate the until recently unexplained thiazide-sensitive electroneutral NaCl reabsorption in the collecting duct (4,11,107). Moreover, pendrin deletion in type B intercalated cells disturbs the function of ENaC in adjacent principal cells (98,100).…”

“…An impressive new study has now established that, in vivo, intercalated cells regulate their intracellular volume by a mechanism involving the vacuolar H 1 -ATPase (H 1 -ATPase; also referred to as V-ATPase in the literature). This study is important because it establishes that although most animal cells rely on the Na 1 /K 1 -ATPase (Na,K-ATPase) to energize other transport processes, intercalated cells instead rely on the H 1 -ATPase (11). Therefore, now it also must be considered that cell types with high H 1 -ATPase levels may use this pump for more than just acid-base regulation.…”