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

### **Tomoaki Ishigami \*, Tabito Kino, Shintaro Minegishi, Naomi Araki, Masanari Umemura, Hisako Ushio, Sae Saigoh and Michiko Sugiyama**

Department of Medical Science and Cardio-Renal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Yokohama, Kanazawa-Ku 236-0004, Japan; kino-tabio@umin.ac.jp (T.K.); shintaro.minegishi@gmail.com (S.M.); naomiaraki@gmail.com (N.A.); umemurma@yokohama-cu.ac.jp (M.U.); hisahisa5172@yahoo.co.jp (H.U.); saesaigo1019@googlemail.com (S.S.); vn\_nv2525smile@yahoo.co.jp (M.S.) **\***Correspondence:tommmish@yokohama-cu.ac.jp;Tel.:+81-45-787-2635(ext.6312)

Received: 19 April 2020; Accepted: 27 May 2020; Published: 29 May 2020

**Abstract:** 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 *Nedd4-2*/*NEDD4L,* 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.

**Keywords:** salt-sensitive hypertension; ubiquitination; Nedd4L/Nedd4-2; epithelial sodium channel; aldosterone sensitive distal nephron; excitation-transcription coupling
