Ed Skolnik and colleagues suggest novel and potentially effective approach to treating ADPKD
Kidney International. 2008 Jun 11. [Epub ahead of print]
KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease.
Albaqumi M, Srivastava S, Li Z, Zhdanova O, Wulff H, Itani O, Wallace DP, Skolnik EY.
[1] Division of Nephrology, New York University School of Medicine, New York, New York, USA
[2] The Skirball Institute, New York University School of Medicine, New York, New York, USA.
Significance:
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic causes of kidney disease and is caused by mutations in one of two genes, PKD1 or PKD2, and is characterized by innumerous fluid-filled kidney cysts. Net fluid secretion into renal cysts is driven by transepithelial Cl- secretion mediated by apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels and is an important factor in kidney enlargement.
In the current study, we found that the K+ channel KCa3.1 plays a critical role in apical Cl- secretion by ADPKD cyst epithelia and that pharmacologic inhibition of KCa3.1 block cyst formation in vitro. Our findings when taken together suggest that pharmacological inhibitors of KCa3.1 may be useful to slow progression of kidney disease patients with ADPKD.
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.Kidney International advance online publication, 11 June 2008; doi:10.1038/ki.2008.246.
PMID: 18547995 [PubMed - as supplied by publisher]