Inhibition of NaPi2a Improves Pressure-Overload Heart Failure and Doxorubicin-Induced Cardiac Damage

Background: Recently, the number of heart failure (HF) patients is increasing worldwide. Based on the success of SGLT2 inhibitor in HF treatment, targeting proximal tubular sodium channel is an attractive therapeutic strategy for HF. We hypothesized that inhibition of Sodium-phosphate co-transporter 2a (NaPi2a), predominantly expressed in the renal proximal tubule, can attenuate the progression of HF via 1) reduction in serum FGF23 levels through phosphate excretion and 2) decrease in fluid volume via sodium excretion. Methods: Using NaPi2a-KO mice, we examined the cardioprotective effect of loss of function of NaPi2a in following HF mouse model; 1) pressure-overload heart failure induced by transverse aortic constriction (TAC), 2) Doxorubicin (Dox) cardiomyopathy and 3) uremic cardiomyopathy by 5/6 nephrectomy Results: In the TAC model, decreased serum phosphate and FGF23, and increased urinary sodium excretion were observed in NaPi2a-KO mice. Left ventricular ejection fraction (LVEF) in echocardiography was preserved in NaPi2a-KO mice. qPCR analysis revealed that upregulation of myocardial injury and fibrosis markers by TAC surgery was ameliorated in NaPi2a-KO mice. In the Dox cardiomyopathy model, LVEF was preserved in NaPi2a-KO mice. qPCR analysis showed that the Dox-induced upregulations of myocardial fibrosis markers were ameliorated in NaPi2a-KO mice. In the uremic cardiomyopathy model, serum phosphate and FGF23 were notable increased, but there were no differences between WT and NaPi2a-KO mice. No significant differences were noted in cardiac function, or expressions of myocardial injury and fibrosis markers by qPCR between the two groups, either. FGF23 levels were not correlated with cardiac contractility in all HF models. Conclusion: NaPi2a inhibition ameliorated the progression of cardiac injury in pressure-overload heart failure and Dox cardiomyopathy but not in uremic cardiomyopathy. Urinary sodium excretion, rather than the decrease in serum FGF23 levels, may involve the effect of NaPi2a inhibition. In the uremic cardiomyopathy model, loss of kidney parenchyma and subsequent high serum phosphorus reduced NaPi2a expression may attributed to the less cardioprotective effect by NaPi2a inhibition. NaPi2a inhibition can be a novel therapeutic candidate for HF especially in the patients with preserved renal function.