Vai trò của WNK trong việc điều chỉnh hoạt động vận chuyển KCl ở tế bào hồng cầu từ những cá nhân bình thường và bệnh nhân mắc bệnh hồng cầu hình liềm

Pflügers Archiv - Tập 471 - Trang 1539-1549 - 2019
David C.-Y. Lu1, Anke Hannemann1, Rasiqh Wadud1, David C. Rees2, John N. Brewin2, Philip S. Low3, John S. Gibson1
1Department of Veterinary Medicine, Cambridge, UK
2Department of Paediatric Haematology, King’s College Hospital, London, UK
3Department of Chemistry, Purdue University, West Lafayette, USA

Tóm tắt

Hoạt động bất thường của hệ vận chuyển KCl (KCC) trong tế bào hồng cầu liên quan đến cơ chế bệnh sinh của bệnh hồng cầu hình liềm (SCA). Sự mất mát chất hòa tan do KCC gây ra làm co lại tế bào, đồng thời tăng nồng độ HbS và thúc đẩy quá trình polymer hóa HbS. KCC trong tế bào hồng cầu cũng phản ứng với nhiều kích thích khác nhau bao gồm pH, thể tích, ure, và áp suất oxy, và sự điều hòa liên quan đến việc phosphoryl hóa protein. Mục tiêu chính của nghiên cứu này là điều tra vai trò của con đường WNK/SPAK/OSR1 trong các tế bào hồng cầu hình liềm. Chất ức chế WNK toàn phần WNK463 kích thích KCC với EC50 là 10,9 ± 1,1 nM và 7,9 ± 1,2 nM ở tế bào hồng cầu hình liềm và tế bào hồng cầu bình thường, tương ứng. Các chất ức chế SPAK/OSR1 có tác động rất nhỏ. Tác động của WNK463 không cộng thêm với các chất ức chế kinase khác (staurosporine và N-ethylmaleimide). Tác động của nó phần lớn bị hủy bỏ bởi việc điều trị trước bằng chất ức chế phosphatase calyculin A. WNK463 cũng làm giảm ảnh hưởng của các kích thích KCC sinh lý (pH, thể tích, ure) và loại bỏ bất kỳ phản ứng nào của KCC đối với sự thay đổi áp suất oxy. Cuối cùng, mặc dù các kinase protein đã được chứng minh có liên quan đến việc điều chỉnh sự phơi bày phosphatidylserine, WNK463 không có tác động. Các phát hiện cho thấy vai trò chủ yếu của WNK trong việc kiểm soát KCC trong các tế bào hồng cầu hình liềm nhưng không có sự tham gia rõ ràng của SPAK/OSR1 ở giai đoạn hạ nguồn. Việc hiểu rõ hơn về các cơ chế sẽ thông tin về bệnh sinh trong khi việc điều chỉnh hoạt động của WNK đại diện cho một phương pháp điều trị tiềm năng.

Từ khóa

#bệnh hồng cầu hình liềm #KCl #hệ vận chuyển #WNK #SPAK #OSR1

Tài liệu tham khảo

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