Abstract 1771: Serum And Glucocorticoid-induced Kinase-1 (SGK-1) Dynamically Regulates Cardiac Fibrosis In A CTGF- Independent Manner
Intro: We previously reported that the mineralcorticoid-responsive kinase, SGK-1, is activated in cardiac hypertrophy and regulates cardiomyocyte (CM) growth and survival. SGK-1 has also been implicated in renal fibrosis through transcriptional induction of connective tissue growth factor (CTGF). In this study, we examined the role of CM SGK-1 activation in the development of cardiac fibrosis.
Methods: We studied histology and electrophysiology in transgenic mice with cardiac-specific overexpression of constitutively-activated (SGK-CA) and kinase-dead (SGK-KD) SGK-1 protein. Protein and RNA expression were measured by Western blot and QRT-PCR, respectively, and SGK-KD mice were studied following transverse aortic constriction (TAC).
Results: EKG analysis revealed QRS prolongation in SGK-CA mice compared with wild type (WT) littermates (22.3±6.6 ms vs. 15.7±4.3 ms, p<0.05), which correlated with increasing age (R2 0.44, p<0.05). Histologically, SGK-CA mice displayed increased fibrosis on Mason’s trichrome stain compared with WT mice. Protein expression of connexin43 (Cx43) was decreased 33% in SGK-CA ventricles (p<0.05), without a change in Cx43 RNA, consistent with post-transcriptional downregulation secondary to fibrosis. TGF-β RNA expression was increased in SGK-CA mice 1.44 fold (p<0.05), as was the fibrosis marker fibronectin (1.22 fold, p<0.05), while CTGF RNA expression was not significantly different between SGK-CA mice and wild type littermates. Following TAC, the SGK-KD mice displayed decreased cardiac fibrosis compared with TAC WT mice. Paradoxically, SGK-KD had increased expression of CTGF RNA vs. WT both at baseline (1.26 fold, p<0.05), as well as after TAC (1.52 fold, p<0.05), with both groups having > 3 fold increase in CTGF RNA after TAC. TGF- β RNA expression also increased about 1.5 fold in each group with TAC, although there was no significant difference between SGK-KD and WT mice either at baseline or after TAC.
Conclusion: Cardiomyocyte SGK-1 activation appears to play a dynamic role in the development of cardiac fibrosis as well as subsequent conduction disease. Our finding of a disconnect between fibrosis and induction of CTGF or TGF- β in SGK mice suggests that it works at least in part through independent pathways.