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 <i>in vivo</i> has remained unclear. We examined this question using <i>Villin-Cre;Sgk1^flox/flox</i> conditional knockout (<i>Sgk1</i>cKO) and littermate heterozygous controls (<i>Sgk1</i>cHET) 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 <i>Sgk1</i>cHET but also in <i>Sgk1</i>cKO. However, only <i>Sgk1</i>cHET exhibited a rise in CFTR-dependent ΔIsc, whereas <i>Sgk1</i>cKO failed to increase secretion despite higher total CFTR. Sgk2 and 3 were upregulated in <i>Sgk1</i>cKO 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.