Col4a3‐/‐ Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over‐Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Abstract

Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3‐/‐ 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 Col4a3‐/‐ mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3‐/‐ 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3‐/‐ mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3‐/‐ 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. How-ever, 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.