**About the Editor**

**Tomoaki Ishigami**, Ph.D.

Associate Professor Department of Medical Science and Cardio-Renal Medicine Yokohama City University Graduate School of Medicine

Dr. Tomoaki Ishigami was born in Tokyo, Japan. He completed his graduation and obtained his medical degree and Ph.D. from the Yokohama City University, Yokohama, Japan. Following this, he moved to the Eccles Institute of Human Genetics, University of Utah, USA, where he worked as a Post-Doctoral Fellow. His primary research interest is elucidating the molecular pathophysiology of salt-sensitive hypertension and atherosclerosis [1–3]. To elucidate the molecular basis of human hypertension, he has used molecular genetic approaches, including single nucleotide polymorphism (SNP) analyses and extensive direct sequencing of candidate genes such as human angiotensinogen [4–6] and human *NEDD4L* [7–9] . Dr. Ishigami and his colleagues revealed that human angiotensinogen gene variants are responsible for human hypertension and appeared according to the migration and selection of human beings globally after leaving Africa, providing substantial evidence supporting the thrifty gene hypothesis for salt-sensitive hypertension [10,11]. Various ion transporters and their accessory proteins expressed along the urinary tubules are biologically responsible for salt sensitivity and salt-sensitive hypertension. Angiotensinogen in proximal tubules and renin in connecting tubules are the two major components of the tubular renin–angiotensin system. The discovery of alternative renin transcripts in the connecting tubules of transgenic mice in 2014 was a landmark achievement for Dr. Ishigami and his team [12]. Furthermore, using extensive direct sequencing, Dr. Ishigami and colleagues reported the molecular diversity of the human *NEDD4L* gene, which is critically involved in epithelial sodium channel ubiquitination [7–9,13,14]. Additionally, using genetically engineered mouse models, direct monitoring of blood pressure via an implantable telemetry system, and detailed metabolic analyses by measurement of urine and food consumption, Dr. Ishigami and colleagues successfully provided direct evidence of the relationship between the lack of a single molecular variant of the ubiquitin ligase gene, *Nedd4-2*, and dietary salt-sensitive hypertension [15–17]. Finally, a review by Dr. Ishigami and colleagues, entitled Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension, was selected to feature in the current Special Issue of *IJMS*, titled Ubiquitination in Health and Disease [18].

1. Chen L, Ishigami T, Nakashima-Sasaki R, Kino T, Doi H, Minegishi S, Umemura S (2016) Commensal Microbe-specific Activation of B2 Cell Subsets Contributes to Atherosclerosis Development Independently of Lipid Metabolism. EBioMedicine 13: 237–247. DOI:10.1016/j.ebiom.2016.10.030.

2. Chen L, Ishigami T (2016) Intestinal Microbiome and Atherosclerosis—Authors' Reply. EBioMedicine 13: 19–20. DOI:10.1016/j.ebiom.2016.10.039.

3. Arakawa K, Ishigami T, Nakai-Sugiyama M, Chen L, Doi H, Kino T, Minegishi S, Saigoh-Teranaka S, Sasaki-Nakashima R, Hibi K, et al. (2019) Lubiprostone as a potential therapeutic agen<sup>t</sup> to improve intestinal permeability and prevent the development of atherosclerosis in apolipoprotein E-deficient mice. PLoS One 14: e0218096. DOI:10.1371/journal.pone.0218096.

4. Ishigami T, Umemura S, Iwamoto T, Tamura K, Hibi K, Yamaguchi S, Nyuui N, Kimura K, Miyazaki N, Ishii M (1995) Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. Circulation 91: 951–954.

5. Ishigami T, Umemura S, Tamura K, Hibi K, Nyui N, Kihara M, Yabana M, Watanabe Y, Sumida Y, Nagahara T, et al. (1997) Essential hypertension and 5' upstream core promoter region of human angiotensinogen gene. Hypertension 30: 1325–1330.

6. Ishigami T, Tamura K, Fujita T, Kobayashi I, Hibi K, Kihara M, Toya Y, Ochiai H, Umemura S (1999) Angiotensinogen gene polymorphism near transcription start site and blood pressure: role of a T-to-C transition at intron I. Hypertension 34: 430–434.

7. Ishigami T, Araki N, Umemura S (2010) Human Nedd4L rs4149601 G allele generates evolutionary new isoform I with C2 domain. Hypertension 55: e10; author reply e11. DOI:10.1161/HYPERTENSIONAHA.109.146738.

8. Ishigami T, Araki N, Minegishi S, Umemura M, Umemura S (2014) Genetic variation in NEDD4L, salt sensitivity, and hypertension: human NEDD4L rs4149601 G allele generates evolutionary new isoform I with C2 domain. J Hypertens 32: 1905. DOI:10.1097/HJH.0000000000000293.

9. Dunn DM, Ishigami T, Pankow J, von Niederhausern A, Alder J, Hunt SC, Leppert MF, Lalouel JM, Weiss RB (2002) Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. J Hum Genet 47: 665–676.

10. Nakajima T, Jorde LB, Ishigami T, Umemura S, Emi M, Lalouel JM, Inoue I (2002) Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. Am J Hum Genet 70: 108–123.

11. Nakajima T, Wooding S, Sakagami T, Emi M, Tokunaga K, Tamiya G, Ishigami T, Umemura S, Munkhbat B, Jin F, et al. (2004) Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world. Am J Hum Genet 74: 898–916

12. Ishigami T, Kino T, Chen L, Minegishi S, Araki N, Umemura M, Abe K, Sasaki R, Yamana H, Umemura S (2014) Identification of bona fide alternative renin transcripts expressed along cortical tubules and potential roles in promoting insulin resistance in vivo without significant plasma renin activity elevation. Hypertension 64: 125–133. DOI:10.1161/HYPERTENSIONAHA.114.03394

13. Araki N, Umemura M, Miyagi Y, Yabana M, Miki Y, Tamura K, Uchino K, Aoki R, Goshima Y, Umemura S, et al. (2008) Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant: implications for essential hypertension. Hypertension 51: 773–777

14. Umemura M, Ishigami T, Tamura K, Sakai M, Miyagi Y, Nagahama K, Aoki I, Uchino K, Rohrwasser A, Lalouel JM, et al. (2006) Transcriptional diversity and expression of NEDD4L gene in distal nephron. Biochem Biophys Res Commun 339: 1129–1137

15. Minegishi S, Ishigami T, Kino T, Chen L, Nakashima-Sasaki R, Araki N, Yatsu K, Fujita M, Umemura S (2016) An isoform of Nedd4-2 is critically involved in the renal adaptation to high salt intake in mice. Sci Rep 6: 27137. DOI:10.1038/srep27137

16. Minegishi S, Ishigami T, Kawamura H, Kino T, Chen L, Nakashima-Sasaki R, Doi H, Azushima K, Wakui H, Chiba Y, et al. (2017) An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities. Int J Mol Sci 18. DOI:10.3390/ijms18061268

17. Kino T, Ishigami T, Murata T, Doi H, Nakashima-Sasaki R, Chen L, Sugiyama M, Azushima K, Wakui H, Minegishi S, et al. (2017) Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice. Int J Mol Sci 18. DOI:10.3390/ijms18061250

18. Ishigami T, Kino T, Minegishi S, Araki N, Umemura M, Ushio H, Saigoh S, Sugiyama M (2020) Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension. Int J Mol Sci 21. DOI:10.3390/ijms21113871
