| First Author | Chen K | Year | 2021 |
| Journal | Redox Biol | Volume | 47 |
| Pages | 102173 | PubMed ID | 34678656 |
| Mgi Jnum | J:324442 | Mgi Id | MGI:6826868 |
| Doi | 10.1016/j.redox.2021.102173 | Citation | Chen K, et al. (2021) Estrogen inhibits renal Na-Pi Co-transporters and improves klotho deficiency-induced acute heart failure. Redox Biol 47:102173 |
| abstractText | OBJECTIVE AND HYPOTHESIS: Klotho is an aging-suppressor gene. Mutation of Klotho gene causes hyperphosphatemia and acute heart failure. However, the relationship of hyperphosphatemia and acute heart failure is unclear. We hypothesize that hyperphosphatemia mediates Klotho deficiency-induced acute heart failure and further that therapeutic reduction of hyperphosphatemia prevents acute heart failure in Klotho mutant (KL(-/-)) mice. METHODS AND RESULTS: A significant elevation of serum phosphorus levels and a large reduction of heart function were found in KL(-/-) mice by six weeks of age. Normalization of serum phosphorus levels by low phosphate diet (LPD) rescued Klotho deficiency-induced heart failure and extended lifespan in male mice. Klotho deficiency impaired cardiac mitochondrial respiratory enzyme function and increased superoxide production, oxidative stress, and cardiac cell apoptosis in male KL(-/-) mice which can be eliminated by LPD. LPD, however, did not rescue hyperphosphatemia or heart failure in female KL(-/-) mice. LPD did not affect estrogen depletion in female KL(-/-) mice. Normalization of serum estrogen levels by treatment with 17beta-estradiol prevented hyperphosphatemia and heart failure in female KL(-/-) mice. Mechanistically, treatment with 17beta-estradiol rescued hyperphosphatemia via inhibiting renal Na-Pi co-transporter expression. Normalization of serum phosphorus levels by treatment with 17beta-estradiol also abolished cardiac mitochondrial respiratory enzyme dysfunction, ROS overproduction, oxidative stress and cardiac cell apoptosis in female KL(-/-) mice. CONCLUSION: Klotho deficiency causes acute heart failure via hyperphosphatemia in male mice which can be prevented by LPD. 17beta-estradiol prevents Klotho deficiency-induced hyperphosphatemia and heart failure by eliminating upregulation of renal Na-Pi co-transporter expression in female mice. |
