Empagliflozin targets a renal neuro-epithelial-immune axis in heart failure
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Background
Persistent neurohormonal activation is a key driver of maladaptive remodeling and disease progression in heart failure (HF). Sodium-glucose cotransporter 2 inhibitors (SGLT2is) confer robust renoprotective effects in HF; however, the extent to which these benefits involve modulation of renal neurohormonal activity remains unclear. We hypothesized that SGLT2i-mediated renoprotection in HF is associated with attenuation of excessive renal neurohormonal activation.
Methods
Male rats with myocardial infarction-induced HF and sham controls were fed standard chow or chow containing empagliflozin (EMPA, 300 mg/kg) for four weeks, followed by assessment of renal inflammatory and neurohormonal markers. Parallel in vitro studies in THP-1 macrophages and HK-2 proximal tubule cells evaluated the direct effects of EMPA on norepinephrine (NE)-dependent tubular inflammatory signaling.
Results
HF rats displayed higher renal cortical renin gene expression and angiotensin II concentrations, which remained unaffected by EMPA. Conversely, EMPA normalized the elevated urinary NE excretion and renal cortical NE content observed in HF rats. Given the inflammatory role of sympathetic hyperactivity, we assessed renal macrophage polarization. EMPA-treated HF rats showed reduced expression of pro-inflammatory markers ( Tnf, Ccr2, Nos2, Il-6 ) and increased expression of markers associated with a reparative macrophage profile ( Arg1, Mrc1, CD163 ), supported by higher CD206⁺ macrophages in kidney sections. While EMPA did not directly alter THP-1 macrophage activation in vitro , it significantly reduced NE-induced SGLT2 expression and interleukin-6 (IL-6) release by HK-2 human proximal tubule epithelial cells.
Conclusion
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.
CLINICAL PERSPECTIVE
What’s new?
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This study identifies a renal neuro-epithelial-immune axis underlying empagliflozin-mediated renoprotection in heart failure.
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Empagliflozin reduces renal cortical and urinary norepinephrine levels in heart failure without altering intrarenal renin-angiotensin system activity, revealing a distinct neurohumoral target of SGLT2 inhibition.
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This sympatholytic effect is associated with a shift in renal macrophages toward a reparative (M2) phenotype, without changes in total macrophage abundance.
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Empagliflozin blocks norepinephrine-induced SGLT2 upregulation, limiting proximal tubular glucose reabsorption and IL-6 production, and linking sympathetic signaling to renal inflammation.
What are the clinical implications?
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Our findings provide a mechanistic basis for the additive cardiorenal benefits of SGLT2 inhibitors in heart failure, beyond conventional RAS-directed therapies.
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Targeting renal sympathetic-driven inflammation may help preserve kidney function and attenuate the progression of cardiorenal syndrome.
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Suppression of a renal neuroinflammatory pathway may help explain the early and sustained benefits of SGLT2 inhibitors across heart failure phenotypes, including nondiabetic patients.
