Paracrine regulation of sodium balance in the distal nephron – RENPAR

The molecular mechanisms underlying salt-sensitivity of blood pressure remain poorly understood in most patients. However, since monogenic forms of impaired blood pressure regulation are caused by defects in renal NaCl absorption in the distal nephron, essential hypertension is likely to be linked to increased NaCl absorption at this site. We recently demonstrated that in the distal nephron ß-intercalated cells (ß-ICs), which until recently were thought to be exclusively involved in acid-base homeostasis, participate in the regulation of Na+ balance by directly absorbing NaCl and by controlling the activity of the Na+ channel ENaC in neighboring principal cells (PCs) through ATP and PGE2 release into the tubular fluid. We also showed that cell swelling of ß-ICs leads to ATP release, which in turn triggers PGE2 release. We propose a new paradigm in which an increase in NaCl delivery to the distal nephron, as a consequence of increased dietary NaCl intake, leads to cell swelling of the ß-ICs, thereby triggering the release of ATP/PGE2, which in turn decrease Na+ absorption and K+ secretion by adjacent PCs. This mechanism is expected to allow the body to get rid of the excess of NaCl brought about by the diet. Members of the WNK (With No lysine (K)) kinases family have been proposed as cell volume sensitive kinases, which reciprocally and coordinately regulate Cl- influx and efflux through phosphorylation/dephosphorylation of Cl- transporters to maintain normal cell volume. We have recently identified WNK4 as a novel regulator of Pendrin, the apical Cl-/HCO3- exchanger accounting for Cl- influx into ß-IC. The activation state of the WNK4 kinase being itself modified in response to changes in extracellular tonicity, we propose that changes in ß-ICs cell volume lead to the modification of the activation state of the WNK4 kinase, promoting changes in Pendrin activity, thereby alterating NaCl transport in ß-ICs. This project combines several experimental approaches including, the use of transgenic mouse models, in vivo physiological analyses using metabolic cages, in vitro microperfusion of isolated cortical collecting ducts for transepithelial ion fluxes determination and fluorescence studies, co-expression studies in heterologous systems, and mass spectrophotometry of proteins or phospho-peptides combined with the use of a COPAS to isolate large quantity of tubular fragments from the cortical collecting duct. This project is expected to dissect the molecular mechanisms of this new paracrine regulatory pathway within the distal nephron, which locally modulates Na+ transport and is critical for normal blood pressure regulation. Deregulation of any of the elements of this regulatory loop is susceptible to have an impact on Na+ absorption and thus on normal blood pressure regulation.