Empagliflozin improves renal and cardiac function in heart failure irrespective of renal SGLT2 expression

Background and Purpose: Heart failure is associated with renal dysfunction suggesting a pathophysiological link between heart and kidney. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, mechanistically, it is unclear if empagliflozin-dependent kidney protection is mediated via inhibition of tubular SGLT2 or more indirectly via improved cardiac function. Interestingly, in the EMPEROR trials, there was a significant interaction of empagliflozin-dependent kidney protection with systolic contractile dysfunction.

We hypothesized that Empagliflozin treatment ameliorates heart failure in response to chronic pressure overload in mice leading to improved renal function.

Methods: Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2-KO). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Cardiac function was evaluated by echocardiography and kidney function by transdermal FITC-Sinistrin measurement (GFR) and urinary albumin/creatinine ratio (UACR).

Results: After 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced left ventricular ejection fraction (LVEF) and diastolic dysfunction. Empagliflozin attenuated changes in LVEF (Fig. A) and improved diastolic dysfunction (data not shown). Interestingly, at 10 weeks, TAC reduced GFR and increased UACR, which was also attenuated by empagliflozin (Fig. B and C). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-KO). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-KO and Empagliflozin prevented this deterioration similar to WT mice (Fig. D vs. A). Surprisingly, Empagliflozin also prevented GFR deterioration 5 weeks after TAC in mice lacking SGLT2 (SGLT2-KO) with comparable magnitude as in WT mice (Fig. E), suggesting that the reno-protective effect of Empagliflozin was independent from SGLT2 inhibition.  A possible mechanism of SGLT2-independent renal protection may involve inhibition of renal inflammation. In accordance, qPCR revealed upregulation of proinflammatory cytokines in kidneys of WT mice, which was diminished by empagliflozin treatment (data not shown).

Conclusion and Outlook: This is the first study investigating the role of SGLT2 in empagliflozin-dependent kidney protection of mice that develop heart failure after TAC. Importantly, empagliflozin treatment prevented deterioration of GFR independent of the presence of SGLT2 possibly by inhibition of renal inflammation.