Na/K-ATPase endocytosis couples pumping and leaking activities in renal epithelial cells: a hypothesis
1Department of Medicine, College of Medicine, University of Toledo, Toledo, Ohio 43614, USA. jiang.liu@utoledo.edu
Abstract:
Renal adaptation to acute or chronic volume expansion as well as dietary sodium intake involves a marked decrease in proximal tubule sodium transport. The precise molecular mechanisms involved in this alteration in proximal tubule sodium transport are still unclear. Low concentration of ouabain, a cardiotonic steroid (CTS) that is a specific inhibitor as well as a ligand of the Na/K-ATPase, has been shown to significantly inhibit transepithelial Na+ transport without altering the intracellular Na+ concentration ([Na+]i) in LLC-PK1 cells. This process is mediated by ouabain-activated signaling pathways that stimulate the endocytosis of the basolateral Na/K-ATPase and down-regulation of apical NHE3 (Na/H exchanger isoform 3). Thus, we propose that CTS, such as ouabain and marinobufagenin (MBG), are intimately involved in renal proximal tubule adaptations to volume expansion. We further speculate that CTS-induced Na/K-ATPase endocytosis couples pumping and leaking activities in renal epithelial cells.
Insights
Cardiotonic steroids (CTS), like ouabain, reduce kidney proximal tubule sodium transport by internalizing Na/K-ATPase. This adaptation is crucial for managing body fluid balance.
Area of Science:
- Nephrology
- Molecular Biology
- Physiology
Background:
- Renal adaptation to volume expansion and sodium intake involves decreased proximal tubule sodium transport.
- The molecular mechanisms underlying this transport alteration remain largely unknown.
Purpose of the Study:
- To investigate the role of cardiotonic steroids (CTS) in renal proximal tubule sodium transport regulation.
- To elucidate the molecular mechanisms by which CTS affect Na/K-ATPase and NHE3 in renal cells.
Main Methods:
- Utilized LLC-PK1 cells to study the effects of low ouabain concentration on transepithelial Na+ transport.
- Investigated changes in intracellular Na+ concentration ([Na+]i) and Na/K-ATPase localization.
- Examined the impact on apical NHE3 expression and activity.
Main Results:
- Low ouabain concentrations inhibited transepithelial Na+ transport without altering intracellular Na+ concentration.
- Ouabain-activated signaling pathways led to basolateral Na/K-ATPase endocytosis.
- Apical NHE3 was down-regulated in response to ouabain treatment.
Conclusions:
- Cardiotonic steroids (CTS), including ouabain and marinobufagenin (MBG), are implicated in renal proximal tubule adaptation to volume expansion.
- CTS-induced Na/K-ATPase endocytosis may link pumping and leaking functions in renal epithelial cells.
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