Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?

Abstract

Gitelman’s syndrome (GS) and Bartter’s 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’s 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’s 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.

ACE2 and SARS-CoV-2 Infection Risk: Insights From Patients With Two Rare Genetic Tubulopathies, Gitelman's and Bartter's Syndromes

“…CQ's negative effects on SARS-CoV's receptor binding, while inhibiting infection ( 25 ), left unaltered ACE2 membrane expression but impaired ACE2's terminal glycosylation via effects on Trans Golgi Network (TNG)/post-Golgi pH homeostasis ( 25 ). The characteristic metabolic alkalosis present in GS/BS patients could reproduce the same, pH dependent, effect(s) on ACE2 glycosylation, thereby impacting not only the GS/BS phenotypes ( 27 ), but also perhaps blocking/inhibiting SARS-CoV-2 binding and thereby reducing COVID-19 infections ( 25 ).…”

“…The increased level of ACE2 and the inhibited ROCK activity of GS/BS ( 4 , 5 , 24 ), both credited with protective effects against COVID-19 infection, may provide a mechanistic basis for our findings. GS/BS patients' characteristic chronic metabolic alkalosis may have altered ACE2's terminal glycosylation in the TGN/endosome system ( 27 ) by blocking its acidification necessary for the ACE2 glycosylation process, thereby blocking/inhibiting SARS-CoV-2 binding and resulting COVID-19 disease. Studies from our laboratory are ongoing to investigate ACE2 glycosylation state as well as other potential GS/BS-related benefits with respect to COVID-19.…”

On the imbalanced protective arm of RAS in COVID‐19: Lesson from rare genetic tubulopathies

“…This effect, while not affecting ACE2 membrane expression, significantly reduced viral binding/infectivity of SARS‐CoV 8 . We suggest that the GS/BS patients’ metabolic alkalosis might increase the endosome pH, mimicking CQ’s and HCQ effect, and thereby bring about aberrant ACE2 glycosylation resulting in an environment hostile also to SARS‐CoV‐2 infection or COVID‐19 symptoms 9 . Of note, both patients treated with CQ and HCQ and GS/BS patients can exhibit a prolonged QT interval, which further suggests that both likely affect similar systems 3,10,11 .…”

“…3 This alkalosis may relate to the effects of Chloroquine (CQ) and hydroxychloroquine (HCQ) affecting ACE2. 8,9 Central to CQ and HCQ effects are that they alkalize the trans-Golgi Network/post-Golgi pathway which then compromises ACE2's glycosylation. This effect, while not affecting ACE2 membrane expression, significantly reduced viral binding/infectivity of SARS-CoV.…”

“…8 We suggest that the GS/BS patients' metabolic alkalosis might increase the endosome pH, mimicking CQ's and HCQ effect, and thereby bring about aberrant ACE2 glycosylation resulting in an environment hostile also to SARS-CoV-2 infection or COVID-19 symptoms. 9 Of note, both patients treated with CQ and HCQ and GS/BS patients can exhibit a prolonged QT interval, which further suggests that both likely affect similar systems. 3,10,11 Whether there is altered ACE2 glycosylation in addition to increased ACE2 found in GS/BS patients is the subject of an ongoing study in our laboratory.…”