Establishment of an Animal Model of Type 2 Cardiorenal Syndrome

ABSTRACT Type 2 cardiorenal syndrome (CRS) is a complex clinical syndrome characterized by chronic kidney injury resulting from chronic cardiac dysfunction. Its underlying pathophysiological mechanisms remain incompletely understood, highlighting the urgent need for disease models that better mimic human pathology and accurately simulate the progression of cardiac‐induced renal injury. Existing models possess significant limitations and often fail to adequately replicate the onset and progression observed in clinical Type 2 CRS patients. We therefore hypothesized that a double‐hit approach combining left anterior descending (LAD) ligation (to induce acute myocardial infarction) with transverse aortic constriction (TAC) (to increase afterload) would produce a model that highly simulates the development and progression of clinical Type 2 CRS, characterized by heart failure and subsequent renal injury. A double‐hit strategy combining LAD ligation and TAC was performed in mice to induce heart failure followed by secondary renal injury. At four post‐operative time points (2 weeks, 4 weeks, 6 weeks, and 8 weeks), we assessed cardiac function, renal function, inflammatory damage, energy metabolism dysfunction, and renal/cardiac fibrosis. Proteomic analysis was additionally performed to characterize molecular changes and identify the optimal model configuration. At week 2, mice developed early‐stage heart failure accompanied by mild kidney inflammation and abnormal energy metabolism. By week 4, these abnormalities progressed to marked inflammation, fibrosis, chronic heart failure, and overt kidney damage. The impairments in energy metabolism, inflammation, and fibrosis peaked at Weeks 6 and 8, leading to severe dysfunction of both the heart and kidneys. This double‐hit model stably recapitulates the natural progression from chronic cardiac dysfunction to chronic kidney injury observed in Type 2 CRS. It therefore serves as a powerful and innovative research platform for in‐depth exploration of the molecular mechanisms underlying Type 2 CRS, screening of potential therapeutic targets, and evaluation of novel interventional strategies.