Gitelman’s and Bartter’s Syndromes: From Genetics to the Molecular Basis of Hypertension and More

Abstract

Background: Gitelman’s and Bartter’s syndromes (GS/BS) are rare genetic tubulopathies characterized by electrolyte imbalance and activation of the renin angiotensin aldosterone system (RAAS). These syndromes have intriguing biochemical and hormonal abnormalities that leads them to be protected from hypertension, cardiovascular and renal remodeling. Summary: In this review we explore the biochemical/molecular mechanisms induced by the activation of the RAAS and its counterregulatory arm which is particularly activated in GS/BS patients, in the context of blood pressure regulation. In addition, we report our findings in the context of COVID-19 pandemic where we observed GS/BS subjects being protected from infection. Key Messages: The intracellular pathways induced by Ang II starting from induction of oxidative stress and vasoconstriction, are crucial for the progression toward cardiovascular-renal remodeling and might be useful targets in order to reduce/halt the progression of Ang II/oxidative stress-induced cardiovascular-renal morbidity in several diseases.

Role of endothelial dysfunction in the severity of COVID‑19 infection (Review)

“…In the alveolar epithelial cells, binding of the viral spike protein to ACE2 reduces the receptor's expression, blocking Ang II conversion to Ang 1-7 and causing Ang II to bind to AT1R, which in turn induces hypokalemia, hyperaldosteronism, proliferation of inflammatory cells, as well as vasoconstriction and fibrosis in severe cases of the disease (30). Notably, loss of ACE2 expression has been shown to result in impaired lung function in mice, via increased vascular permeability, pulmonary edema and neutrophil accumulation (31).…”

Oxidants and Cardiorenal Vascular Remodeling—Insights from Rare Genetic Tubulopathies: Bartter’s and Gitelman’s Syndromes

“…The overactivation of the RAS with concomitant reduced peripheral resistance, normal to low blood pressure and the absence of cardiovascular/renal remodeling, are the counterintuitive clinical features of GSBS patients ( Figure 1 B) [ 3 , 4 ].…”

“… Angiotensin II signaling in chronic kidney disease and hypertension versus angiotensin II signaling in GSBS [ 3 , 4 , 15 ]. Panel ( A ).…”

“…This altered electrolyte trafficking gives rise to renin-angiotensin system (RAS) overactivation. However, strikingly, these patients have normo- or hypotension and do not exhibit the cardiovascular–renal remodeling classically associated with arterial hypertension [ 3 , 4 ]. Furthermore, in addition to the activation of multiple pathways in RAS, like those found in hypertension, they unexpectedly exhibit increased antioxidant defenses, as well.…”

“…Furthermore, in addition to the activation of multiple pathways in RAS, like those found in hypertension, they unexpectedly exhibit increased antioxidant defenses, as well. Given these seeming paradoxes, BSGS patients represent an extraordinary opportunity in a human model to uncover and assess potential interventions of RAS- and oxidative stress (OxSt)-related cardiovascular and renal remodeling pathways [ 3 , 4 ].…”