Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Redox Biol. 2021 Nov;47:102173. doi: 10.1016/j.redox.2021.102173. Epub 2021 Oct 18.
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.
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 17β-estradiol prevented hyperphosphatemia and heart failure in female KL(-/-) mice. Mechanistically, treatment with 17β-estradiol rescued hyperphosphatemia via inhibiting renal Na-Pi co-transporter expression. Normalization of serum phosphorus levels by treatment with 17β-estradiol also abolished cardiac mitochondrial respiratory enzyme dysfunction, ROS overproduction, oxidative stress and cardiac cell apoptosis in female KL(-/-) mice.
Klotho deficiency causes acute heart failure via hyperphosphatemia in male mice which can be prevented by LPD. 17β-estradiol prevents Klotho deficiency-induced hyperphosphatemia and heart failure by eliminating upregulation of renal Na-Pi co-transporter expression in female mice.
Klotho 是一种衰老抑制基因。Klotho 基因突变会导致高磷血症和急性心力衰竭。然而，高磷血症和急性心力衰竭之间的关系尚不清楚。我们假设高磷血症介导 Klotho 缺乏诱导的急性心力衰竭，进一步假设降低高磷血症可预防 Klotho 突变（KL(-/-)) 小鼠的急性心力衰竭。
在 6 周龄时，KL(-/-) 小鼠的血清磷水平显著升高，心脏功能明显降低。通过低磷饮食（LPD）使血清磷水平正常化可挽救 Klotho 缺乏引起的心力衰竭并延长雄性小鼠的寿命。Klotho 缺乏会损害心脏线粒体呼吸酶功能并增加超氧化物产生、氧化应激和心脏细胞凋亡，这些可以通过 LPD 消除。然而，LPD 不能挽救雌性 KL(-/-) 小鼠的高磷血症或心力衰竭。LPD 不影响雌性 KL(-/-) 小鼠的雌激素耗竭。用 17β-雌二醇治疗使血清雌激素水平正常化可预防雌性 KL(-/-) 小鼠的高磷血症和心力衰竭。从机制上讲，用 17β-雌二醇治疗可通过抑制肾脏 Na-Pi 共转运体的表达来纠正高磷血症。用 17β-雌二醇使血清磷水平正常化还消除了雌性 KL(-/-) 小鼠心脏线粒体呼吸酶功能障碍、ROS 过度产生、氧化应激和心脏细胞凋亡。
Klotho 缺乏导致雄性小鼠急性心力衰竭通过高磷血症，可通过 LPD 预防。17β-雌二醇通过消除肾脏 Na-Pi 共转运体表达的上调来预防 Klotho 缺乏诱导的高磷血症和心力衰竭。
