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Renal Klotho safeguards platelet lifespan in advanced chronic kidney disease through restraining Bcl-xL ubiquitination and degradation.
Journal of Thrombosis and Haemostasis : JTH 2022 September 11
BACKGROUND: Thrombosis and hemorrhage as two opposite pathologies are prevalent within the chronic kidney disease (CKD) population. Platelet homeostasis, which positions centrally in their pathogenesis, varies among the CKD population, while the underlying mechanism is poorly understood.
OBJECTIVE: To investigate the change character and mechanism of platelet homeostasis in CKD and its association with renal Klotho deficiency.
METHODS: The change character of platelet homeostasis and its association with renal Klotho deficiency were determined based on a cohort study as well as CKD mice and Klotho-deficient mice with CKD. The effects on thrombopoiesis and platelet lifespan were examined by flow cytometry and platelet transfer. The underlying mechanism was explored by proteomics, flow cytometry, western blot, and immunoprecipitation.
RESULTS: We show that platelet count declines both in patient and mouse model with advanced CKD (Adv-CKD) and is positively associated with circulating Klotho levels. Mechanistically, we identify that ubiquitin ligase UBE2O governs Bcl-xL ubiquitination and degradation in platelets, whereas Adv-CKD-induced oxidative stress in platelets stimulates p38MAPK to promote Bcl-xL phosphorylation, which facilitates UBE2O binding to Bcl-xL and subsequent Bcl-xL degradation. Consequently, platelet lifespan is shortened in Adv-CKD, culminating in platelet count decline. However, kidney-secreted soluble Klotho protein restricts oxidative stress in platelets, thereby preserving Bcl-xL expression and platelet lifespan.
CONCLUSIONS: Our findings uncover the mechanism of platelet count decline in Adv-CKD and identify renal Klotho as a long-range regulator of platelet lifespan, which not only provide a molecular mechanism underlying CKD-associated thrombocytopenia and hemorrhage but also offer a promising therapy choice.
OBJECTIVE: To investigate the change character and mechanism of platelet homeostasis in CKD and its association with renal Klotho deficiency.
METHODS: The change character of platelet homeostasis and its association with renal Klotho deficiency were determined based on a cohort study as well as CKD mice and Klotho-deficient mice with CKD. The effects on thrombopoiesis and platelet lifespan were examined by flow cytometry and platelet transfer. The underlying mechanism was explored by proteomics, flow cytometry, western blot, and immunoprecipitation.
RESULTS: We show that platelet count declines both in patient and mouse model with advanced CKD (Adv-CKD) and is positively associated with circulating Klotho levels. Mechanistically, we identify that ubiquitin ligase UBE2O governs Bcl-xL ubiquitination and degradation in platelets, whereas Adv-CKD-induced oxidative stress in platelets stimulates p38MAPK to promote Bcl-xL phosphorylation, which facilitates UBE2O binding to Bcl-xL and subsequent Bcl-xL degradation. Consequently, platelet lifespan is shortened in Adv-CKD, culminating in platelet count decline. However, kidney-secreted soluble Klotho protein restricts oxidative stress in platelets, thereby preserving Bcl-xL expression and platelet lifespan.
CONCLUSIONS: Our findings uncover the mechanism of platelet count decline in Adv-CKD and identify renal Klotho as a long-range regulator of platelet lifespan, which not only provide a molecular mechanism underlying CKD-associated thrombocytopenia and hemorrhage but also offer a promising therapy choice.
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