Genetic deletion of the sodium phosphate cotransporter NaPi2a ameliorates heart failure in mice.

Apical membrane sodium transporters in renal proximal tubules, such as sodium-glucose co-transporter 2, are attractive therapeutic targets for the treatment of heart failure (HF). Sodium-phosphate co-transporter 2a (NaPi2a) is predominantly expressed in the apical membrane of proximal tubular epithelia and functions to reabsorb filtered phosphate and sodium. It currently remains unclear whether the inhibition of NaPi2a attenuates HF. We found that NaPi2a deficiency improved the cardiac phenotypes of the HF models of transverse aortic constriction (TAC) and doxorubicin (Dox) cardiotoxicity. Natriuretic and phosphaturetic effects were observed in NaPi2a-KO mice under normal conditions, resulting in low serum phosphate and fibroblast growth factor-23 (FGF23) levels. In the TAC and Dox models, the left ventricular ejection fraction was preserved in NaPi2a-KO mice, while FGF23 levels did not correlate with cardiac hypertrophy. A qPCR analysis of heart tissue showed increases in the mRNA expression of fetal myocardial and tissue fibrosis markers in the TAC and Dox models, and decreases in NaPi2a-KO mice. The present results demonstrated that NaPi2a-mediated natriuresis, rather than decreases in serum FGF23 levels through its phosphaturic effects, may be responsible for attenuating myocardial injury and cardiac tissue fibrosis in the TAC and Dox-induced HF models in NaPi2a-KO mice.