{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T14:45:24Z","timestamp":1777646724170,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,7]],"date-time":"2020-08-07T00:00:00Z","timestamp":1596758400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gitelman\u2019s syndrome (GS) and Bartter\u2019s syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS\/BS patients as nature\u2019s experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS\/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine\/hydroxychloroquine and its effects. Of specific interest are chloroquine\/hydroxychloroquine\u2019s ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN\/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN\/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN\/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.<\/jats:p>","DOI":"10.3390\/ijms21165660","type":"journal-article","created":{"date-parts":[[2020,8,7]],"date-time":"2020-08-07T09:30:54Z","timestamp":1596792654000},"page":"5660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Are the Clinical Presentations (Phenotypes) of Gitelman\u2019s and Bartter\u2019s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their \u201cpH\u201d Enotype?"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7534-0128","authenticated-orcid":false,"given":"Lorenzo A","family":"Cal\u00f2","sequence":"first","affiliation":[{"name":"Nephrology, Dialysis and Transplantation Unit, Department of Medicine, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul A","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of California at Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1097\/HJH.0000000000000321","article-title":"Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long-term sequelae: Insights from Bartter\u2019s and Gitelman\u2019s syndromes, human models of endogenous angiotensin II signaling antagonism","volume":"32","author":"Davis","year":"2014","journal-title":"J. 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