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Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical <i>Col4a3^-/-</i> model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in <i>Col4a3^-/-</i> mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male <i>Col4a3^-/-</i> 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C <i>Col4a3^-/-</i> mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 <i>Col4a3^-/-</i> mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS.