Sex-specific responses in the early stages of diet-induced cardiovascular-kidney-metabolic syndrome

Despite established sex differences in cardiovascular-kidney-metabolic (CKM) syndrome, sex-based treatment approaches remain lacking, partly due to limited appropriate female animal models. This study characterized sex differences in cardiorenal phenotype associated with a high-fat diet (HFD) intervention in mice and additionally assessed the impact of the sodium glucose cotransporter 2 inhibitor, dapagliflozin, a therapy previously shown to improve cardiorenal outcomes in patients. Chow or HFD (60% kJ lipids) commenced at 6 wk of age in male and female C57BL/6J mice. At 18 wk of age, HFD mice were randomized to 8 wk of dapagliflozin (2.5 mg/kg/day) or vehicle (20% Trappsol) treatment via subcutaneous osmotic minipumps. Metabolic phenotype and cardiac function were assessed pretreatment and at endpoint, with cardiac and renal pathophysiology measured using tissue collected at study end. HFD-induced elevations in percentage fat mass were more pronounced in female mice, accompanied by modest impairments in left ventricular systolic function and alterations in the cardiac lipidome and metabolome. In the kidney, sex differences were also apparent in renal structure and remodeling, mitochondrial function and markers of oxidative stress, incretin receptors, and sodium solute carriers (at the transcriptomic level). Plasma concentrations of dapagliflozin did not reach target levels in either sex; low-dose treatment improved glucose tolerance and circulating creatinine levels only in male HFD mice. In conclusion, although only a modest impact of HFD and dapagliflozin was observed, sex differences in the early development of CKM syndrome were apparent in male and female mice.NEW & NOTEWORTHY High-fat diet (HFD) feeding exerts modest cardiometabolic dysfunction in mice, with changes more apparent in female mice. Dapagliflozin treatment exerts sex-specific effects on glucose tolerance and measures of renal injury, even at lower doses, in males. Female mice are more prone to renal dysfunction, indicating the importance of interrogating sex differences in animal models and treatments for cardiovascular-kidney-metabolic (CKM) syndrome.