Estrogen inhibits renal Na-Pi Co-transporters and improves klotho deficiency-induced acute heart failure,Redox Biology

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Estrogen inhibits renal Na-Pi Co-transporters and improves klotho deficiency-induced acute heart failure
Redox Biology ( IF 10.7 ) Pub Date : 2021-10-18 , DOI: 10.1016/j.redox.2021.102173
Kai Chen ₁ , Zhongjie Sun ₁

Affiliation

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 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.

Conclusion

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.

中文翻译：

雌激素抑制肾脏 Na-Pi 协同转运蛋白并改善 klotho 缺乏引起的急性心力衰竭

目标和假设

Klotho是一种抗衰老基因。Klotho基因的突变导致高磷血症和急性心力衰竭。然而，高磷血症与急性心力衰竭的关系尚不清楚。我们假设高磷血症介导 Klotho 缺乏症引起的急性心力衰竭，并且进一步降低高磷血症可预防 Klotho 突变体 (KL(-/-)) 小鼠的急性心力衰竭。

方法和结果

KL(-/-) 小鼠在六周龄时发现血清磷水平显着升高和心脏功能大幅下降。通过低磷酸盐饮食 (LPD) 使血清磷水平正常化可挽救 Klotho 缺乏症引起的雄性小鼠心力衰竭并延长其寿命。在雄性 KL(-/-) 小鼠中，Klotho 缺乏会损害心脏线粒体呼吸酶功能，并增加超氧化物的产生、氧化应激和心脏细胞凋亡，这些可通过 LPD 消除。然而，LPD 并没有挽救雌性 KL(-/-) 小鼠的高磷血症或心力衰竭。LPD 不影响雌性 KL(-/-) 小鼠的雌激素消耗。通过用 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。机械地，通过抑制肾脏 Na-Pi 协同转运蛋白的表达。通过用 17β-雌二醇处理使血清磷水平正常化也消除了雌性 KL(-/-) 小鼠的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。