Abstract 364: Klotho Gene Deficiency Causes Heart Failure via Disruption of Phosphate Metabolism

Heart failure is the major cause of mortality for patients with chronic kidney damage (CKD). Although a decrease in plasma klotho levels has been linked to chronic kidney disease (CKD), the relationship between Klotho and heart failure is unclear. Here, using Klotho mutant homozygous (KL -/-) mice, we found that Klotho deficiency caused hyperphosphatemia and heart failure. Normalization of serum phosphorous by dietary phosphate restriction rescued Klotho deficiency-induced heart failure in male mice. However, low phosphate diet did not rescue hyperphosphatemia and heart failure in KL (-/-) female mice. Therefore, hyperphosphatemia may be an important mechanism of Klotho deficiency-induced heart failure. Dietary phosphate restriction did not prevent estrogen depletion in KL (-/-) female mice, suggesting that estrogen depletion may involve in Klotho deficiency induced hyperphosphatemia and heart failure. Normalization of serum estrogen level by 17β-estradiol prevented cardiac remodeling and heart dysfunction in KL (-/-) female mice. Moreover, treatment with 17β-estradiol normalized phosphate metabolism via regulating renal NaPi co-transporter expression. Treatment with 17β-estradiol abolished mitochondrial dysfunction and cardiac apoptosis in Klotho deficient mice. This study demonstrates for the first time that hyperphosphatemia is an important mediator of heart failure which can be prevented by dietary phosphate restriction in male KL (-/-) mice. Estrogen deficiency mediates hyperphosphatemia leading to heart failure due to klotho deficiency in female mice.