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

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 ?1 isoform of Na/K-ATPase causes a reduction in CD40 while rescue of the ?1 but not the ?2 isoform restores CD40 expression in renal epithelial cells. Second, because the major functional difference between ?1 and ?2 is the ability of ?1 to form a functional signaling complex with Src, we examined whether the Na/K-ATPase/Src complex is important for CD40 expression. We show that a gain-of-Src binding ?2 mutant restores CD40 expression while loss-of-Src binding ?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.

SUBMITTER: Xie JX 

PROVIDER: S-EPMC6031043 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature