Combined Empagliflozin and Sacubitril/Valsartan Therapy Additively Improves Cardiorenal Function Through <scp>AMPK</scp> Activation and Angiotensin <scp>II</scp> Type 1 Receptor Signaling Attenuation in a Rat Model of Cardiorenal Syndrome

Cardiorenal syndrome (CRS) is characterized by a bidirectional impairment of cardiac and renal function, associated with high mortality and limited effective therapeutic options. This study evaluated the cardiorenal protective effects of combined sodium-glucose cotransporter-2 inhibition (empagliflozin) and angiotensin receptor-neprilysin inhibition (sacubitril/valsartan) in an experimental model of CRS. Adult Sprague-Dawley rats were subjected to 5/6 nephrectomy and doxorubicin administration, followed by a high-protein diet to induce CRS. Animals were randomized to receive empagliflozin, sacubitril/valsartan, a combination of both agents, and no treatment for 60 days. Endpoints included survival, assessment of cardiorenal function, circulating biomarkers, histopathological analysis, and evaluation of signaling pathways implicated in fibrosis, oxidative stress, and inflammation. Combination therapy resulted in a 60-day survival rate of 89%, compared to 50% in untreated controls and 75%-78% with either monotherapy. All active treatments significantly preserved both cardiac and renal function, reduced levels of oxidized low-density lipoproteins, and attenuated interstitial fibrosis by inhibiting the TGF-β/Smad3 pathway. Furthermore, these therapies activated the AMPK-PGC-1α-SIRT1 signaling axis and suppressed angiotensin II/AT1 receptor signaling, resulting in decreased reactive oxygen species and inflammatory mediators, including NOX2, NOX4, IL-6, IL-1β, TNF-α, and phosphorylated NF-κB. Across all evaluated parameters, combination therapy consistently demonstrated the most pronounced protective effects. Collectively, these findings provide compelling preclinical evidence that concomitant administration of empagliflozin and sacubitril/valsartan confers superior cardiorenal protection and enhances survival in a rodent CRS model, supporting further clinical investigation of this combinatory therapeutic approach.