Increased Na+/H+ exchanger activity on the apical surface of a cilium-deficient cortical collecting duct principal cell model of polycystic kidney disease

Academic Article

Abstract

  • Pathophysiological anomalies in autosomal dominant and recessive forms of polycystic kidney disease (PKD) may derive from impaired function/ formation of the apical central monocilium of ductal epithelia such as that seen in the Oak Ridge polycystic kidney or orpk (Ift88 ) mouse and its immortalized cell models for the renal collecting duct. According to a previous study, Na/H exchanger (NHE) activity may contribute to hyperabsorptive Na movement in cilium-deficient ("mutant") cortical collecting duct principal cell monolayers derived from the orpk mice compared with cilium-competent ("rescued") monolayers. To examine NHE activity, we measured intracellular pH (pH ) by fluorescence imaging with the pH-sensitive dye BCECF, and used a custom-designed perfusion chamber to control the apical and basolateral solutions independently. Both mutant and rescued monolayers exhibited basolateral Na -dependent acid-base transporter activity in the nominal absence of CO /HCO . However, only the mutant cells displayed appreciable apical Na -induced pH recoveries from NH prepulse-induced acid loads. Similar results were obtained with isolated, perfused collecting ducts from orpk vs. wild-type mice. The pH dependence of basolateral cariporide/HOE-694-sensitive NHE activity under our experimental conditions was similar in both mutant and rescued cells, and 3.5- to 4.5-fold greater than apical HOE-sensitive NHE activity in the mutant cells (pH 6.23-6.68). Increased apical NHE activity correlated with increased apical NHE1 expression in the mutant cells, and increased apical localization in collecting ducts of kidney sections from orpk vs. control mice. A kidney-specific conditional cilium-knockout mouse produced a more acidic urine compared with wild-type littermates and became alkalotic by 28 days of age. This study provides the first description of altered NHE activity, and an associated acid-base anomaly in any form of PKD. © 2012 the American Physiological Society. Tg737Rpw + + - + + i 2 3 i 4 i i
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    Author List

  • Olteanu D; Liu X; Liu W; Roper VC; Sharma N; Yoder BK; Satlin LM; Schwiebert EM; Bevensee MO
  • Volume

  • 302
  • Issue

  • 10