SGK1 signaling: an important modulator of CFTR function and early immune response in mouse intestine

Glucocorticoid (GC) and stress-induced SGK1 signaling rapidly modulate intestinal epithelial transport, yet whether epithelial SGK1 is required to couple GC signaling to functional CFTR output in vivo has remained unclear. We examined this question using Villin-Cre;Sgk1 flox/flox conditional knockout ( Sgk1cKO) and littermate heterozygous controls ( Sgk1cHET) mice treated with dexamethasone (DEX; 2mg/kg i.p.) for 1h or 4h. Outcomes included CFTR protein abundance, immunolocalization (immunoblotting and immunofluorescence), CFTR-ion transport measured by short-circuit current (Isc) in Ussing chambers, epithelial Sgk1/2/3 expression, intestinal loop fluid accumulation, and CD45 + cell signal as a readout of early immune engagement. Acute DEX treatment activated SGK1 signaling and elevated CFTR protein in Sgk1cHET but also in Sgk1cKO. However, only Sgk1cHET exhibited a rise in CFTR-dependent ΔIsc, whereas Sgk1cKO failed to increase secretion despite higher total CFTR. Sgk2 and 3 were upregulated in Sgk1cKO but did not restore function. CD45 + signal rose transiently at 1h and normalized by 4h, consistent with early, self-limited immune engagement. In an intestinal loop assay, short-term DEX treatment did not exacerbate cGMP-evoked fluid accumulation. Together, these data identify epithelial SGK1 signaling as a necessary node that translates acute stress-induced CFTR stabilization into functional secretion and a transient epithelial-immune response. These findings help reconcile expression-function discrepancies and suggest that targeting SGK1 or its downstream steps may be required to achieve functional CFTR gains under acute stress in the intestine.