Abstract 4147456: Serum and Glucocorticoid Regulated Kinase 1 (SGK1) Inhibition Induces Anti-Fibrotic and Anti-Inflammatory Responses: Relevance to Cardiac Fibrosis

Background: Cardiac fibrosis is a condition characterized by deposition of extracellular matrix proteins and myofibroblasts, leading to scar formation, cardiac dysfunction and arrhythmogenesis. Various cardiometabolic stressors can promote fibrosis and scarring, including MI, hypertension, diabetes and obesity. Targeted therapy to prevent cardiac fibrosis is therefore an important unmet medical need. In a mouse model of obesity-related atrial fibrillation (AF), inhibition of SGK1 reduced markers of inflammation and fibrosis, suggesting SGK1 as a novel target. Several SGK1 inhibitors are being evaluated in clinical studies for the treatment of long QT syndrome, paroxysmal AF, and heart failure. Hypothesis: SGK1 activation is a significant driver of inflammation and fibrosis, and its inhibition may offer a new therapeutic strategy for treating fibrotic diseases, including those of the cardiovascular system. Methods: Primary hepatic stellate cells, lung fibroblasts, and proximal tubule cells were treated with TGFβ for 24-48 hours to induce fibrosis and measure the effects of SGK1 inhibition on markers of fibrosis (alpha SMA and collagen 1). Three, selective and potent, SGK1 inhibitors (SGK1-I 1,2,3) were tested in a BioMAP fibrosis panel at concentrations ranging from 0.3 to 10 µM. The fibrosis panel includes three systems that model TGFβ and TNFα driven myofibroblast differentiation during chronic inflammation and wound healing. Markers of fibrosis, tissue remodeling, myofibroblast activation, and inflammation were measured quantitatively. IC50s were determined using GraphPad Prism. Results: In primary human stellate cells, SGK1-I,1,2,3 inhibited αSMA and collagen 1 mRNAs with IC50s ranging from 0.1- 0.8 µM and 1.0-3.0 µM, respectively. In primary lung fibroblasts, treatment with SGK1-I reduced the mRNA and protein expression of αSMA. Treatment of cells from different tissues with TGFβ resulted in a 1.5-to-3.0-fold increase in SGK1 mRNA and protein and this was blocked by the TGFβ receptor inhibitor SB525334. SGK1 inhibitors displayed anti-inflammatory and anti-fibrotic properties in the BioMAP panel, with inhibition of IL-6, IL-8, MCP-1, and αSMA, collagen 1, and TIMP1 respectively. Conclusion: SGK1 is an important effector of TGFβ signaling. The development of SGK1 inhibitors may represent a new therapeutic strategy for treating fibrotic diseases. Additional studies are warranted to further evaluate novel SGK1 inhibitors in cardiac fibrosis