Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension

• Published in: International journal of molecular sciences 2020-05, Vol.21 (11), p.3871
• Main Authors: Ishigami, Tomoaki, Kino, Tabito, Minegishi, Shintaro, Araki, Naomi, Umemura, Masanari, Ushio, Hisako, Saigoh, Sae, Sugiyama, Michiko
• Format: Article
• Language: English
• Subjects: Aldosterone; Aldosterone - metabolism; aldosterone sensitive distal nephron; Animals; Biological activity; Blood pressure; Cardiovascular diseases; Cell cycle; Cell surface; Electrolytes; Enzymes; epithelial sodium channel; Epithelial Sodium Channels - genetics; Epithelial Sodium Channels - metabolism; excitation-transcription coupling; Genetic analysis; Genetic engineering; Hormones; Humans; Hypertension; Hypertension - metabolism; Kidney Tubules, Distal - metabolism; Kinases; Nedd4 Ubiquitin Protein Ligases - genetics; Nedd4 Ubiquitin Protein Ligases - metabolism; Nedd4L/Nedd4-2; Nephrons; Pathogenesis; Physiology; Post-translation; Proteasomes; Proteins; Regulation; Review; Salt; salt-sensitive hypertension; Sodium; Sodium channels; Sodium Chloride - metabolism; Therapeutic applications; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Urine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21113871

Ubiquitination is a representative, reversible biological process of the post-translational modification of various proteins with multiple catalytic reaction sequences, including ubiquitin itself, in addition to E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, E3 ubiquitin ligase, deubiquitinating enzymes, and proteasome degradation. The ubiquitin-proteasome system is known to play a pivotal role in various molecular life phenomena, including the cell cycle, protein quality, and cell surface expressions of ion-transporters. As such, the failure of this system can lead to cancer, neurodegenerative diseases, cardiovascular diseases, and hypertension. This review article discusses / an E3-ubiquitin ligase involved in salt-sensitive hypertension, drawing from detailed genetic dissection analysis and the development of genetically engineered mice model. Based on our analyses, targeting therapeutic regulations of ubiquitination in the fields of cardio-vascular medicine might be a promising strategy in future. Although the clinical applications of this strategy are limited, compared to those of kinase systems, many compounds with a high pharmacological activity were identified at the basic research level. Therefore, future development could be expected.