Combined Empagliflozin and Sacubitril/Valsartan Therapy Additively Improves Cardiorenal Function Through AMPK Activation and Angiotensin II Type 1 Receptor Signaling Attenuation in a Rat Model of Cardiorenal Syndrome
Abstract
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…
Read the paper
Related studies
- The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity
- Hypoglycemic medicines in the treatment of Alzheimer’s disease: Pathophysiological links between AD and glucose metabolism
- Isorhamnetin Reduces Glucose Level, Inflammation, and Oxidative Stress in High-Fat Diet/Streptozotocin Diabetic Mice Model
- Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease—From Bench to Bedside
- Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis
- Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.