Circulating soluble urokinase-type plasminogen activator receptor reflects disease severity in a mouse model of diabetic kidney disease and heart failure with preserved ejection fraction

Abstract

Circulating biomarkers are increasingly used for patient risk stratification in chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF). However, clinically relevant circulating biomarkers remain insufficiently characterized in rodent models recapitulating diabetic cardiorenal disease with HFpEF. To address this gap, we evaluated 20 translationally relevant inflammation-associated biomarkers in the diabetic db/db uninephrectomized (UNx)-ReninAAV mouse model of CKD and HFpEF. db/db UNx-ReninAAV mice exhibited marked increases in circulating soluble urokinase-type plasminogen activator receptor (suPAR) and monocyte chemoattractant protein-1 (MCP-1), and in interleukin 10 (IL-10) at late stages of disease. Histological analyses confirmed increased tissue expression of suPAR in the heart and kidney and of MCP-1 in the heart. Notably, circulating suPAR levels correlated with disease severity, including systolic and diastolic cardiac dysfunction and albuminuria. Together, these results provide a systematic analysis of biomarkers in a rodent model of diabetes, CKD and HFpEF and identify suPAR as the biomarker most closely associated with disease severity.