Effects of the serine/threonine kinase SGK1 on the epithelial Na+ channel (ENaC) and CFTR: Implications for cystic fibrosis

Cystic fibrosis (CF) is characterized by impaired Cl-secretion and increase d Na+ reabsorption in several tissues including respiratory epithelium. Man y CFTR mutations have been identified over the past years. However, only a poor correlation between the genotype and lung phenotype was found suggesti ng additional factors influencing the phenotype and course of the disease. The serine/threonine kinase SGK1 has recently been shown to stimulate the a ctivity of the epithelial Na+ channel ENaC. A variety of stimuli such as al dosterone, cell shrinkage, insulin or TGF-beta1 stimulate transcription and activate the SGK1 kinase. Here we further examined the effects of SGK1 on ENaC and CFTR which have mutual interactions and we analyzed sgk1 mRNA abun dance in lung tissue from CF patients. Coexpression of CFTR and h-SGK1 in X enopus oocytes increased ENaC currents as previously described. In addition CFTR mediated currents were also stimulated. h-SGK1 accelerated the expres sion of the amiloride sensitive Na+-current in Xenopus oocytes paralleled b y increased ENaC-protein abundance in the oocyte membrane, an effect which was reversed by a h-SGK1(K127R) mutation lacking the ATP-binding site. The cation selectivity or Na+ affinity were not affected. However, coexpression of h-SGK1 with ENaC altered the sensitivity of the Na-channel to the inhib itors amiloride and triamterene. The inhibitory effect of CFTR expression o n ENaC current was not affected by coexpression of h-SGK1 in Xenopus oocyte s. Lung tissue from CIF patients strongly expressed the serine/threonine ki nase h-sgk1 which was not the case for non-CIF lung tissue. Loss of CFTR fu nction itself in a CIF lung epithelial cell line did not increase SGK1 expr ession. In summary, enhanced expression of h-SGK1 in epithelial cells of CF -lung tissue may be a novel pathophysiological factor contributing to incre ased Na+ channel activity and thus to increased Na+ transport in CF. Copyri ght (C) 2001 S. Karger AG, Basel.