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

Ravarotto, Verdiana; Bertoldi, Giovanni; Stefanelli, Lucia Federica; Nalesso, Federico; Calò, Lorenzo A.

doi:10.1159/000526070

Cited by 8 publications

(8 citation statements)

References 59 publications

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“…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).…”

Section: Raasmentioning

confidence: 99%

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

et al. 2022

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COVID-19 patients with severe infection have been observed to have elevated auto-antibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G protein-coupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL-6, IL-8 and TNF-α) by immune cells. Despite the presence of AAs in severe COVID-19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and renin-angiotensin-aldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID-19. Contents1. Introduction 2. How does vasoconstriction occur? 3. Endothelin and endothelin receptors 4. RAAS 5. NO 6. AT1R and ETAR auto-antibodies 7. Conclusions

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Section: Raasmentioning

confidence: 99%

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

et al. 2022

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“…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 ].…”

Section: Ras and Ros In Gitelman’s And Bartter’s Syndrome Patientsmentioning

confidence: 99%

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

Section: Figurementioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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Two human genetic tubulopathies, Bartter’s (BS) and Gitelman’s (GS) syndromes, have normo/hypotension and absent cardiac remodeling despite their apparent angiotensin system (RAS) activation. This seeming contradiction has led to an extensive investigation of BSGS patients, the result of which is that BSGS represents a mirror image of hypertension. BSGS’s unique set of properties has then permitted their use as a human model to probe and characterize RAS system pathways and oxidative stress in cardiovascular and renal remodeling and pathophysiology. This review details the results using GSBS patients that provide a deeper understanding of Ang II signaling and its associated oxidants/oxidative stress in humans. By providing a more complete and complex picture of cardiovascular and renal remodeling pathways and processes, studies of GSBS can inform the identification and selection of new targets and therapies to treat these and other oxidant-related disorders.

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SLC12A1 variant c.1684+1 G>A causes Bartter syndrome type 1 by promoting exon 13 skipping

Yang,

Li,

Guo

et al. 2024

Nephrology

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BackgroundBartter syndrome type 1, an autosomal recessive genetic disorder, is caused by pathogenic loss‐of‐function variants in the SLC12A1 gene. It is characterized by metabolic alkalosis and prenatal‐onset polyuria leading to polyhydramnios.MethodsWe identified pathogenic gene in a 12‐day‐old newborn boy with Bartter syndrome type 1 using whole‐exome sequencing. Sanger sequencing validated the identified variants. A minigene assay was performed to investigate the effect of a novel splice site variant on pre‐mRNA splicing.ResultsWe found a compound heterozygous variants in the SLC12A1 gene, consisting of a known pathogenic missense mutation (NM_000338: c.769 G>A; p.Gly257Ser) and a novel splice site variant (c.1684+1 G>A). In silico predictions and an in vitro minigene splicing assay demonstrated that the splicing variant c.1684+1 G>A abolished a consensus splice donor site of SLC12A1 intron 13, resulting in complete exon 13 skipping, translational frameshift, and premature termination codon, ultimately leading to loss of SLC12A1 function.ConclusionUsing a cell‐based in vitro assay, we revealed the aberrant effect of the pathogenic splicing variant SLC12A1 c.1684+1 G>A on pre‐mRNA splicing. Our findings expand the gene mutation spectrum of Bartter syndrome type 1, providing a basis for genetic diagnosis and the development of genetic medicines.image

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

Cited by 8 publications

References 59 publications

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

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

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

SLC12A1 variant c.1684+1 G>A causes Bartter syndrome type 1 by promoting exon 13 skipping

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