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 high fat diet (HFD) intervention in mice, and additionally assessed the impact of the sodium glucose co-transporter 2 inhibitor (SGLT2i), dapagliflozin, a therapy previously shown to improve cardiorenal outcomes in patients. Chow or HFD (60% kJ lipids) commenced at 6 weeks of age in male and female C57BL/6J mice. At 18 weeks of age, HFD mice were randomized to 8 weeks of dapagliflozin (2.5 mg/kg/day) or vehicle (20% Trappsol®) treatment via s.c. osmotic mini-pumps. Metabolic phenotype and cardiac function were assessed pre-treatment 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 modest impact of HFD and dapagliflozin were observed, sex differences in the early development of CKM syndrome were apparent in male and female mice.