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. 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.

• Authors: Camila I Irion, Monique Williams, Jose Condor Capcha, Trevor Eisenberg, Guerline Lambert, Lauro M Takeuchi, Grace Seo, Keyvan Yousefi, Rosemeire Kanashiro-Takeuchi, Keith A Webster, Karen C Young, Joshua M Hare, Lina A Shehadeh
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 12 (Jun 15 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35743114 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Autoantigens
• Collagen Type IV
• Slc5a2 protein, mouse
• Sodium-Glucose Transporter 2
• type IV collagen alpha3 chain

Topics

• Animals
• Autoantigens (metabolism)
• Collagen Type IV (metabolism)
• Disease Models, Animal
• Female
• Heart Failure
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Nephritis, Hereditary (genetics)
• Phenotype
• Sodium-Glucose Transporter 2 (genetics, metabolism)
• Stroke Volume