PKD and CF: An interesting family provides insight into the molecular pathophysiology of polycystic kidney disease

Cotton, CU; Avner, E. D.

doi:10.1016/s0272-6386(98)70088-5

Cited by 10 publications

(9 citation statements)

References 11 publications

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“…Our studies suggest that CF carriers (ϩ/Ϫ) also may have a somewhat milder clinical PKD course, although the effect could be difficult to detect and quantify, but it also should be noted that patients who have ADPKD and co-inheriting CF are not completely protected from cystic disease (27,28,68), suggesting that non-CFTR-based mechanisms may be present to allow cyst growth in ADPKD.…”

Section: Discussionmentioning

confidence: 80%

Early Embryonic Renal Tubules of Wild-Type and Polycystic Kidney Disease Kidneys Respond to cAMP Stimulation with Cystic Fibrosis Transmembrane Conductance Regulator/Na+,K+,2Cl− Co-Transporter–Dependent Cystic Dilation

Magenheimer¹,

John

Isom

et al. 2006

Journal of the American Society of Nephrology

120

124

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Section: Discussionmentioning

confidence: 80%

Early Embryonic Renal Tubules of Wild-Type and Polycystic Kidney Disease Kidneys Respond to cAMP Stimulation with Cystic Fibrosis Transmembrane Conductance Regulator/Na+,K+,2Cl− Co-Transporter–Dependent Cystic Dilation

Magenheimer¹,

John

Isom

et al. 2006

Journal of the American Society of Nephrology

120

124

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“…9,11 We used here an established neonatal kidney organ culture model to test the efficacy of PPQ-102 to reduce cyst volume. Intact kidney models to study cystogenesis, although technically more difficult than cell culture models such as MDCK cells grown in collagen gels, are superior in recapitulating native kidney anatomy and cellular phenotype.…”

Section: Discussionmentioning

confidence: 99%

Nanomolar Potency Pyrimido-pyrrolo-quinoxalinedione CFTR Inhibitor Reduces Cyst Size in a Polycystic Kidney Disease Model

et al. 2009

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Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of ~110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347 analogues established structure–activity relationships. The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido-[4′,5′-3,4]pyrrolo[1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC50 ~90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date.

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“…Enhanced cAMP-induced Cl -secretion [50] through CFTR is implicated in fluid secretion by renal cysts in autosomal dominant polycystic kidney disease (ADPKD). A role for CFTR in autosomal recessive PKD is less certain, since cystic disease progression in a mouse model of ARPKD was not influenced by loss of CFTR (BPK mouse crossed with the CFTR knockout mouse) [51,52]. This finding suggests that other non-CFTR Clchannels expressed in renal collecting duct principal cells may compensate for loss of CFTR.…”

Section: Cystic Fibrosis Transmembrane Conductance Regulator (Cftr)mentioning

confidence: 99%

Role of kidney chloride channels in health and disease

Veizis

Cotton

2007

Pediatr Nephrol

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Chloride channels are expressed along the entire mammalian nephron. They participate in transepithelial chloride transport, cell volume regulation and acidification of intracellular vesicles. Some chloride channels are constitutively active and others are regulated by either second messengers such as cAMP or Ca(++) or secondary to changes in membrane potential. The molecular identities of a number of chloride channels within the kidney are still unknown. Abnormalities in chloride channel expression and function in the kidney can cause a range of disorders such as autosomal recessive Dent's disease, Bartter's syndrome, renal tubular acidosis and diabetes insipidus. The purpose of this review is to give an overview of the chloride channels in the kidney and to focus on the function of renal chloride channels as revealed by diseases associated with channel dysfunction.

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PKD and CF: An interesting family provides insight into the molecular pathophysiology of polycystic kidney disease

Cited by 10 publications

References 11 publications

Early Embryonic Renal Tubules of Wild-Type and Polycystic Kidney Disease Kidneys Respond to cAMP Stimulation with Cystic Fibrosis Transmembrane Conductance Regulator/Na+,K+,2Cl− Co-Transporter–Dependent Cystic Dilation

Early Embryonic Renal Tubules of Wild-Type and Polycystic Kidney Disease Kidneys Respond to cAMP Stimulation with Cystic Fibrosis Transmembrane Conductance Regulator/Na+,K+,2Cl− Co-Transporter–Dependent Cystic Dilation

Nanomolar Potency Pyrimido-pyrrolo-quinoxalinedione CFTR Inhibitor Reduces Cyst Size in a Polycystic Kidney Disease Model

Role of kidney chloride channels in health and disease

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