Both the wild type and a functional isoform of CFTR are expressed in kidney

Morales, Marcelo M.; Carroll, Tiziana Piazza; Morita, Takashi; Schwiebert, Erik M.; Devuyst, Olivier; Wilson, Patricia D.; Lopes, Anibal Gil; Stanton, Bruce A.; Dietz, Harry C.; Cutting, Garry R.; Guggino, William B.

doi:10.1152/ajprenal.1996.270.6.f1038

Cited by 97 publications

(130 citation statements)

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“…Studies in cystic fibrosis have suggested that the CFTR is an important downregulator of sodium channel activity in nasal epithelium (15). Expression of the CFTR has been demonstrated in human renal epithelia but its influence on renal channel activity is not clear (16,17). Our findings of a significant detectable increase in sodium channel activity in nasal epithelia of patients with Liddle's syndrome despite the regulatory effects of CFTR therefore suggest that sodium channel activity in renal tubules of these patients will also be significantly increased.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Baker¹,

Jeunemaı̂tre²,

Portal³

et al. 1998

J. Clin. Invest.

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In Liddle's syndrome, a rare inherited form of hypertension, epithelial sodium channel mutations appear to cause high blood pressure by increasing sodium reabsorption through sodium channels in the renal distal tubule. This increase in channel activity has not been confirmed previously by in vivo measurement. We have made transnasal potential difference measurements (effective in detection of increased sodium channel activity in cystic fibrosis) in three brothers with genetically proven Liddle's syndrome, their unaffected sister, and 40 normotensive controls. Maximum potential difference after 2 wk off treatment in the affected brothers was Ϫ 30.4 Ϯ 1.2 mV (values mean Ϯ SD, lumen-negative with respect to submucosa) and was significantly more lumen-negative than that of the control group ( Ϫ 18.6 Ϯ 6.8 mV, P ϭ 0.0228) or the unaffected sister ( Ϫ 18.25 mV, P Ͻ 0.01). The change in potential difference after topical application of 10 Ϫ 4 M amiloride was greater in the Liddle's patients, 14.0 Ϯ 2.1 mV, than in controls (7.9 Ϯ 3.9 mV, P ϭ

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Section: Discussionmentioning

confidence: 99%

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Baker¹,

Jeunemaı̂tre²,

Portal³

et al. 1998

J. Clin. Invest.

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“…The number of active CFTR channels also is known to be regulated by cAMP-dependent vesicle trafficking, as well as by correct glycosylation (2,35). Third, the discrete nature of renal manifestations in CF might be due to tissue-specific protective mechanisms, such as the occurrence of functional CFTR splice variants (7,8), or alternative pathways for chloride (4). …”

Section: Studies In Clcn5mentioning

confidence: 99%

“…During human nephrogenesis, CFTR is expressed in the apical membrane of the branching ureteric bud and, later, in the apical pole of proximal tubule (PT) cells in the cortex, where it remains detected after birth (5,6). A functional truncated isoform also has been described in the kidney, with a distinct ontogeny pattern and a minor plasma membrane expression (7,8). Despite the high level of CFTR expression in the developing and mature kidney, no overwhelming renal phenotype has been associated with CF (4,9).…”

mentioning

confidence: 99%

Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Jouret¹,

Bernard²,

Hermans³

et al. 2007

Journal of the American Society of Nephrology

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Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF).Although CFTR is expressed in the kidney, no overwhelming renal phenotype has been documented in patients with CF. This study investigated the expression, subcellular distribution, and processing of CFTR in the kidney; used various mouse models to assess the role of CFTR in proximal tubule (PT) endocytosis; and tested the relevance of these findings in patients with CF. The level of CFTR mRNA in mouse kidney approached that found in lung. CFTR was located in the apical area of PT cells, with a maximal intensity in the straight part (S3) of the PT. Fractionation showed that CFTR co-distributed with the chloride/proton exchanger ClC-5 in PT endosomes. Cftr ؊/؊ mice showed impaired 125 I-␤ 2 -microglobulin uptake, together with a decreased amount of the multiligand receptor cubilin in the S3 segment and a significant loss of cubilin and its low molecular weight (LMW) ligands into the urine. Defective receptor-mediated endocytosis was found less consistently in Cftr ⌬F/⌬F mice, characterized by a large phenotypic heterogeneity and moderate versus mice that lacked ClC-5. A significant LMW proteinuria (and particularly transferrinuria) also was documented in a cohort of patients with CF but not in patients with asthma and chronic lung inflammation. In conclusion, CFTR inactivation leads to a moderate defect in receptor-mediated PT endocytosis, associated with a cubilin defect and a significant LMW proteinuria in mouse and human. The magnitude of the endocytosis defect that is caused by CFTR versus ClC-5 loss likely reflects functional heterogeneity along the PT.

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“…CFTR-driven fluid and electrolyte secretion by these cells flushes mucins and antimicrobial factors from submucosal glands onto the surface epithelium where they play important roles in mucociliary clearance and host defence. 19 In the kidney, CFTR is differentially expressed along the length of the nephron, 20 where it serves several functions. First, CFTR acts as a regulated anion channel to transport Cl -across the apical membrane of epithelial cells in different nephron segments.…”

Section: The Physiology Of Cftrmentioning

confidence: 99%

The Therapeutic Potential of Small-molecule Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− Channel

Liu

Cami‐Kobeci

Wang

et al. 2014

Ion Channel Drug Discovery

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The cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in fluid and electrolyte movements across ducts and tubes lined by epithelia. Loss of CFTR function causes the common life-limiting genetic disease cystic fibrosis (CF) and a spectrum of disorders termed CFTR-related diseases, while unphysiological CFTR activity characterises secretory diarrhoea and autosomal dominant polycystic kidney disease (ADPKD). The prevalence of these disorders argues persuasively that small-molecule CFTR modulators have significant therapeutic potential. Here, we discuss how knowledge and understanding of the CFTR Cl− channel, its physiological role and malfunction in disease led to the development of the CFTR potentiator ivacaftor, the first small molecule targeting CFTR approved as a treatment for CF. We consider the prospects for developing other therapeutics targeting directly CFTR including CFTR correctors to rescue the apical membrane expression of CF mutants, CFTR corrector-potentiators, dual-acting small-molecules to correct the processing and gating defects of F508del-CFTR, the commonest CF mutant and CFTR inhibitors to prevent fluid and electrolyte loss in secretory diarrhoea and cyst swelling in ADPKD. The success of ivacaftor provides impetus to other CFTR drug development programmes and a paradigm for the creation of therapeutics targeting the root cause of other genetic disorders.

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Both the wild type and a functional isoform of CFTR are expressed in kidney

Cited by 97 publications

References 0 publications

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Abnormalities of nasal potential difference measurement in Liddle's syndrome.

Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

The Therapeutic Potential of Small-molecule Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− Channel

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