Effects of NKCC2 isoform regulation and NaCl transport in the thick ascending limb and macula densa cells: a modeling study.

This study aims to understand the extent to which modulation of NKCC2 differential splicing affects NaCl delivery to the macula densa. NaCl absorption by the thick ascending limb and macula densa cells is mediated by the apical Na+-K+-2Cl- cotransporter NKCC2. A recent study has indicated that differential splicing by NKCC2 is modulated by dietary salt (Schiebl et al., Am J Physiol Renal Physiol, 2013). Given the markedly different ion affinities of its splice variants, modulation of NKCC2 differential splicing is believed to impact NaCl reabsorption. To assess the validity of that hypothesis, we have developed a mathematical model of the macula densa cell transport, and incorporated that cell model into a previously-applied model of the thick ascending limb (Weinstein, Am J Physiol Renal Physiol, 2010). The macula densa model predicts a 27.4 and 13.1~mV depolarization of the basolateral membrane (as a surrogate for activation of tubuloglomerular feedback, TGF) when luminal [NaCl] is increased from 25 to 145~mM or luminal [K+] is increased from 1.5 to 3.5~mM, respectively, consistent with experimental measurements. Simulations indicate that with luminal solute concentrations consistent with in vivo conditions near the macula densa, NKCC2 operates near its equilibrium state. Results also suggest that modulation of NKCC2 differential splicing by low salt, which induces a shift from NKCC2-A to NKCC2-B primarily in the cortical thick ascending limb and macula densa cells, signifi...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research