The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis

Shiuan-Chen Lin; Chun Ma; Kao-Jung Chang; Han-Ping Cheong; Ming-Cheng Lee; Yuan-Tzu Lan; Chien-Ying Wang; Shih-Hwa Chiou; Teh-Ia Huo; Tsui-Kang Hsu; Ping-Hsing Tsai; Yi-Ping Yang

doi:10.3390/biomedicines10092169

The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis

Biomedicines. 2022 Sep 2;10(9):2169. doi: 10.3390/biomedicines10092169.

Authors

Shiuan-Chen Lin^{1

2}, Chun Ma^{3

4}, Kao-Jung Chang^{1

2

4}, Han-Ping Cheong^{2

5}, Ming-Cheng Lee^{6

7}, Yuan-Tzu Lan^{1

8}, Chien-Ying Wang^{1

9

10

11}, Shih-Hwa Chiou^{2

3

5

12

13}, Teh-Ia Huo^{2

5}, Tsui-Kang Hsu¹⁴, Ping-Hsing Tsai^{2

5}, Yi-Ping Yang^{1

2

15}

Affiliations

¹ School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
² Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
³ School of Medicine, National Taiwan University, Taipei 10617, Taiwan.
⁴ Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
⁵ Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
⁶ Department of Medicine, Cheng Hsin General Hospital, Taipei 11220, Taiwan.
⁷ Division of Infectious Diseases, Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei 11220, Taiwan.
⁸ Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
⁹ Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
¹⁰ Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
¹¹ Department of Physical Education and Health, University of Taipei, New Taipei 10478, Taiwan.
¹² Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
¹³ Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan.
¹⁴ Department of Ophthalmology, Cheng Hsin General Hospital, Taipei 11220, Taiwan.
¹⁵ Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.

Abstract

The with-no-lysine (WNK) kinase family, comprising four serine-threonine protein kinases (WNK1-4), were first linked to hypertension due to their mutations in association with pseudohypoaldosteronism type II (PHAII). WNK kinases regulate crucial blood pressure regulators, SPAK/OSR1, to mediate the post-translational modifications (PTMs) of their downstream ion channel substrates, such as sodium chloride co-transporter (NCC), epithelial sodium chloride (ENaC), renal outer medullary potassium channel (ROMK), and Na/K/2Cl co-transporters (NKCCs). In this review, we summarize the molecular pathways dysregulating the WNKs and their downstream target renal ion transporters. We summarize each of the genetic variants of WNK kinases and the small molecule inhibitors that have been discovered to regulate blood pressure via WNK-triggered PTM cascades.

Keywords: ENaC; NCC; NKCCs; PHAII; ROMK; SPAK/OSR1; UMOD; WNK kinase; blood pressure regulation; post-translational modifications.

Publication types

Review

Grants and funding

This research was funded by the Ministry of Science and Technology (MOST 110-2320-B-075-008), Taipei Veterans General Hospital (V111B-016 and V111B-022), Yen Tjing Ling Medical Foundation (CI-111-23 and CI-111-32), and Joint Projects of National Yang Ming Chiao Tung University and Cheng-Hsin General Hospital (CY11012 and CY11114), Taiwan.