Na/K-ATPase/src complex mediates regulation of CD40 in renal parenchyma

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Abstract
Background. Recent studies have highlighted a critical role for CD40 in the pathogenesis of renal injury and fibrosis. However, little is currently understood about the regulation of CD40 in this setting. Methods. We use novel Na/K-ATPase cell lines and inhibitors in order to demonstrate the regulatory function of Na/K-ATPase with regards to CD40 expression and function. We utilize 5/6 partial nephrectomy as well as direct infusion of a Na/K-ATPase ligand to demonstrate this mechanism exists in vivo. Results. We demonstrate that knockdown of the alpha 1 isoform of Na/K-ATPase causes a reduction in CD40 while rescue of the alpha 1 but not the alpha 2 isoform restores CD40 expression in renal epithelial cells. Second, because the major functional difference between alpha 1 and alpha 2 is the ability of alpha 1 to form a functional signaling complex with Src, we examined whether the Na/KATPase/Src complex is important for CD40 expression. We show that a gain-of-Src binding alpha 2 mutant restores CD40 expression while loss-of-Src binding alpha 1 reduces CD40 expression. Furthermore, loss of a functional Na/K-ATPase/Src complex also disrupts CD40 signaling. Importantly, we show that use of a specific Na/K-ATPase/Src complex antagonist, pNaKtide, can attenuate cardiotonic steroid (CTS)-induced induction of CD40 expression in vitro. Conclusions. Because the Na/K-ATPase/Src complex is also a key player in the pathogenesis of renal injury and fibrosis, our new findings suggest that Na/K-ATPase and CD40 may comprise a pro-fibrotic feed-forward loop in the kidney and that pharmacological inhibition of this loop may be useful in the treatment of renal fibrosis.
Funding Information
  • American Heart Association (13POST16860035, 12SDG12050473)
  • National Institutes of Health (1RO1HL105649, 1RO1HL137004)
  • David and Helen Boone Foundation Research Fund
  • Central Society for Clinical and Translational Research
  • University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center

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