Cytokines and sodium induce protein kinase A-dependent cell-surface Na,K-ATPase recruitment via dissociation of NF-{kappa}B/I{kappa}B/protein kinase A catalytic subunit complex in collecting duct principal Cells

Policlinico S.Orsola-Malpighi, Bolonia, Emilia-Romagna, Italy
Journal of the American Society of Nephrology (Impact Factor: 9.34). 10/2005; 16(9):2576-85. DOI: 10.1681/ASN.2005040448
Source: PubMed


Collecting duct (CD) principal cells are exposed to large physiologic variations of apical Na+ influx as a result of variations of Na(+) intake and extrarenal losses. It was shown previously that increasing intracellular [Na+] induces recruitment of Na,K-ATPase to the cell surface in a protein kinase A (PKA)-dependent manner in both native and cultured renal CD principal cells. As described previously in response to cytokines in nonrenal cells, PKA activation in response to increased intracellular [Na+] was independent of cAMP and required proteasomal activity. With the use of cultured mpkCCD(cL4) cells as a model of CD principal cells, whether cytokines and increased intracellular [Na+] share a common signaling pathway leading to cell-surface Na,K-ATPase recruitment was investigated. Results showed that two potent inducers of NF-kappaB, LPS and TNF-alpha, enhance Na+ transport and induce cell-surface Na,K-ATPase recruitment in mpkCCD(cL4) cells via cAMP-independent PKA activation. In addition, increased intracellular [Na+] after selective plasma membrane permeabilization by a low concentration of the Na+ ionophore amphotericin B (1 microg/ml) induced dissociation of the PKA catalytic subunit from p65-NF-kappaB and IkappaBalpha. Moreover, inhibitors of NF-kappaB/IkappaB dissociation prevented both Na+-dependent stimulation of PKA activity and cell-surface Na,K-ATPase recruitment. Altogether, these results revealed the presence of a novel Na+-dependent intracellular signaling pathway leading to Na,K-ATPase cell-surface recruitment via dissociation of the PKA catalytic subunit from a macromolecular complex that contains NF-kappaB and IkappaBalpha in CD epithelial cells.

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