KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease

Mamdouh Albaqumi, Shekhar Srivastava, Zhai Li, Olga Zhdnova, Heike Wulff, Omar Itani, Darren P. Wallace, Edward Y. Skolnik

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by numerous fluid-filled kidney cysts. Net fluid secretion into renal cysts is caused by transepithelial transport mediated by the apical cystic fibrosis transmembrane conductance regulator chloride channel, which leads to cyst enlargement. Here we found that forskolin, a potent adenylyl cyclase agonist, stimulated anion secretion by monolayers of kidney cells derived from patients with ADPKD. TRAM-34, a specific KCa3.1 potassium channel blocker, inhibited this current, and in vitro cyst formation and enlargement by the cells cultured within a collagen gel. Net chloride secretion was enhanced by the KCa3.1 activator DCEBIO and both chloride secretion and in vitro cyst growth were inhibited by overexpression of myotubularin-related protein-6, a phosphatase that specifically inhibits KCa3.1 channel activity. Our study suggests that KCa3.1 channels play a critical role in transcellular chloride secretion and net fluid transport into the kidney cysts of patients with ADPKD by maintaining the electrochemical driving force for chloride efflux through apical chloride channels. Pharmacological inhibitors of KCa3.1 channels may provide a novel and effective therapy to delay progression to kidney failure in patients with ADPKD.

Original languageEnglish (US)
Pages (from-to)740-749
Number of pages10
JournalKidney International
Volume74
Issue number6
DOIs
StatePublished - Sep 2008

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Autosomal Dominant Polycystic Kidney
Potassium Channels
Cysts
Chlorides
Growth
Kidney
Fluids and Secretions
Chloride Channels
Cell Enlargement
Potassium Channel Blockers
Cystic Fibrosis Transmembrane Conductance Regulator
Colforsin
Adenylyl Cyclases
Renal Insufficiency
Anions
Cultured Cells
Collagen
Gels
Pharmacology

Keywords

  • ADPKD
  • Calcium-activated K channels
  • CFTR
  • KCa3.1

ASJC Scopus subject areas

  • Nephrology

Cite this

KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease. / Albaqumi, Mamdouh; Srivastava, Shekhar; Li, Zhai; Zhdnova, Olga; Wulff, Heike; Itani, Omar; Wallace, Darren P.; Skolnik, Edward Y.

In: Kidney International, Vol. 74, No. 6, 09.2008, p. 740-749.

Research output: Contribution to journalArticle

Albaqumi, Mamdouh ; Srivastava, Shekhar ; Li, Zhai ; Zhdnova, Olga ; Wulff, Heike ; Itani, Omar ; Wallace, Darren P. ; Skolnik, Edward Y. / KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease. In: Kidney International. 2008 ; Vol. 74, No. 6. pp. 740-749.
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