Integrated analysis reveals neuro-immune pathway in the central nervous system that supports SGLT2i`s protective effects in treatment of cardiac remodeling

Background: Growing evidence are showing beneficial effects of sodium glucose transport protein 2 inhibitors (SGLT2i) in treatment of heart failure, but underlying neurogenic mechanism remains unclear. In this study the effect of empagliflozin (EM) on sympatho-excitation and potential neurogenic mechanism for EM`s therapeutic effects on cardiac remodeling were studied. Methods: Deoxycorticosterone acetate (DOCA)-salt and high-salt (8%) diet (HSD) mouse models were utilized. Single-cell RNA sequencing was used to explore the mechanism by which SGLT2 inhibitors improve cardiac remodeling in hypertension. Meanwhile, blood samples were collected from hospitalized patients diagnosed with heart failure to verify the results of animal studies. Results: In DOCA-salt or HSD treated mice, EM was associated with a protective, blood pressure-independent effect on cardiac remodeling. Both DOCA-salt and HSD induced sympatho-excitation, together with neuronal hyper-activity in the pre-autonomic regions of brain, and these were blunted in mice with EM co-treatment. Additionally, single-nucleus RNA sequencing using hypothalami indicated that cellular interplays among the vessels, microglia and inhibitory neurons were involved in the disease- and EM-associated actions. Notably, DOCA-salt or HSD treatment induced peripheral immune activation, including lymphocytosis and elevated plasma interferon-{gamma}, which likely mediated the disease-associated state transition of microglia. Differentially expressed genes in neurons highlighted that EM abolished disease-associated upregulation of protein ubiquitination, which might support imbalance of presympathetic excitatory/inhibitory tones, and vasopressin production. In patients` blood samples, EM was associated with significant elevation of hematocrit value in all groups, and reduction of lymphocytes counts in the patients with high NT-proBNP value (> 2550 pg/mL, no diuretic co-treatment). Conclusions: Empagliflozin attenuates cardiac remodeling in hypertensive mice independently of blood pressure lowering. This protection is associated with reduced sympathetic activity and restored microglial homeostasis, suggesting a potential neuro-immune role for SGLT2 inhibitors in treating hypertensive cardiac injury.