Empagliflozin targets a renal neuro-epithelial-immune axis in heart failure

Persistent neurohormonal activation drives maladaptive remodeling and disease progression in heart failure (HF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors confer robust renoprotective effects in HF, but whether these effects involve modulation of renal neurohormonal activity remains unclear. We tested the hypothesis that SGLT2 inhibitor-mediated renoprotection in HF is associated with attenuation of excessive renal neurohormonal activation. Male rats with myocardial infarction-induced HF and sham controls were treated with standard chow or empagliflozin (EMPA, 300 mg/kg) for 4 wk. Parallel in vitro studies using THP-1 macrophages (a human acute monocytic leukemia cell line) and HK-2 proximal tubule cells evaluated the direct effects of EMPA and/or norepinephrine (NE)-dependent tubular inflammatory signaling. HF was associated with higher renal cortical renin expression and angiotensin II levels, which were not modified by EMPA. In contrast, EMPA normalized the elevated urinary norepinephrine (NE) excretion and renal cortical NE content observed in HF. Given the inflammatory role of sympathetic hyperactivity, we assessed renal macrophage activation. EMPA-treated HF rats showed reduced expression of proinflammatory markers [tumor necrosis factor (Tnf), C-C motif chemokine receptor 2 (Ccr2), nitric oxide synthase 2 (Nos2), and Interleukin-6 (Il-6)] and increased expression of markers associated with a reparative macrophage profile [Arginase 1 (Arg1), Mannose receptor C-type 1 (Mrc1), and CD163 (Cd63)], supported by higher CD206⁺ macrophages in kidney sections. Although EMPA did not directly alter THP-1 macrophage activation, it significantly reduced NE-induced SGLT2 expression and interleukin-6 (IL-6) release by HK-2 human proximal tubule epithelial cells. These findings support a model in which SGLT2 inhibitors confer renoprotection in HF by suppressing renal sympathetic hyperactivity, independently of the intrarenal renin-angiotensin system, thereby disrupting a maladaptive renal neuro-epithelial-immune axis and promoting a reparative macrophage phenotype.NEW & NOTEWORTHY Our findings identify a renal neuro-epithelial-immune axis that may, at least in part, underlie empagliflozin-mediated renoprotection in heart failure. Empagliflozin selectively attenuated surrogate markers of renal sympathetic activity, lowering cortical and urinary norepinephrine without detectable changes in intrarenal renin-angiotensin system components. These changes were accompanied by a shift toward a reparative macrophage phenotype. In vitro, empagliflozin blocked norepinephrine-induced SGLT2 upregulation and IL-6 production, linking sympathetic signaling to tubular inflammation.