Abstract Body: Background: Cardiovascular Kidney Metabolic Syndrome (CKMD) remains a major contributor to morbidity despite existing therapies, underscoring the need for novel targets. Increased expression of SGK1 promotes adverse remodeling triggering inflammation, and fibrosis. Building on our prior demonstration that a potent, selective SGK1 inhibitor (SGK1i) mitigates heart failure-related cardiac abnormalities and reduces hypertension and albuminuria in the Dahl salt-sensitive model (DSS), we next evaluated its cardiorenal effects using transcriptomic and histopathologic endpoints.
Hypothesis: SGK1 inhibition mediates cardiac and renal protection in DSS rats on a high salt diet (HSD).
Methods: Male Dahl SS rats (n=40) received a 0.3% low salt diet (LSD) or 8% NaCl diet (HSD) for 12 weeks. After 6 weeks, rats were administered vehicle or a SGK1i (10 or 25 mg/kg/day, p.o.) for the next 6 weeks. Renal and cardiac histopathology were evaluated by Periodic Acid–Schiff/Masson’s Trichrome staining. Bulk RNA-Seq, DESeq2, and GSEA identified differentially expressed genes (DEG) and regulated pathways.
Results: HSD induced marked glomerulosclerosis, mesangiolysis, and acute tubular injury vs LSD controls. SGK1i dose-dependently reduced glomerular and tubular damage toward LSD levels; 10 and 25 mg/kg doses of SGK1i lowered injury scores 40–60% relative to vehicle treated HSD rats. GSEA confirmed HSD-induced renal inflammation, macrophage infiltration, and upregulation of EMT, TGFβ signaling, and loss of mitochondrial integrity. These were dose-dependently mitigated by SGK1i (FDR < 0.05). Similar results were detected in the heart where SGK1i decreased signatures of macrophage invasion, inflammation, fibrosis, and restored mitochondrial integrity. DEG included canonical markers of heart and kidney damage, Nppa and Kim-1, respectively, that were significantly attenuated by SGK1i.
Conclusions: In the DSS model, SGK1 inhibition attenuates renal fibrosis and reprograms kidney and cardiac transcriptomes, reversing HSD-induced inflammatory, profibrotic, and metabolic pathway disturbances towards the low-salt state. These findings suggest SGK1 is a compelling target for integrated CKMD protection and support its continued clinical development.