ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: PO1256

Identification of CLC-5, the Electrogenic 2Cl-/H+ Exchanger, as the Dominant Apical Chloride Secreting Transporter in Kidney Cyst Epithelium in Tuberous Sclerosis

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Barone, Sharon L., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Brooks, Marybeth, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Bissler, John J., Le Bonheur Children's Hospital and St. Jude Children's Research Hospital, Memphis, Tennessee, United States
  • Yu, Jane J., University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
  • Zahedi, Kamyar A., University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Soleimani, Manoocher, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States

Cyst expansion in Tuberous Sclerosis Complex (TSC) or PKD requires secretion of chloride into the cyst lumen as the driving mechanism for salt accumulation. In PKD, Cl- secretion into the cyst lumen is mediated via the cAMP/PKA-stimulation of CFTR in principal cells consequent to the V2 receptor activation by AVP. Kidney cystogenesis in TSC differs from PKD in that cyst epithelia in TSC is comprised of genotypically normal A-intercalated cells, which do not exhibit noticeable expression of either CFTR or the V2 receptor. The identity of the Cl- secreting molecule(s) in TSC cyst epithelia remains unknown. Based on RNA Seq analysis in kidneys of Tsc1 KO mice, we hypothesized that the chloride transporter ClC-5 is expressed on the apical membrane of A-intercalated cells in cyst epithelia of humans and animal models of TSC. CLC-5 is a 2Cl-/H+ exchanger that is located in collecting duct A-intercalated cells where it is predominantly localized to endosomes and plays a critical role in dissipating H+ secretion and membrane depolarization by H+-ATPase. This allows parallel movement of Cl- and H+ into the endosomes.


Double immunofluorescent studies utilizing CLC-5 and H+-ATPase antibodies were performed on kidney tissue from mice with principal cell inactivation of Tsc1 (Tsc1/Aqp2 Cre), pericyte inactivation of Tsc1 (Tsc1/Renin Cre), principal cell inactivation of Tsc-2 (Tsc2/Aqp2 Cre), global heterozygous Tsc2 (Tsc2+/-) and cysts from TSC patients.


Double immunofluorescence labeling demonstrated remarkable co-localization of CLC-5 and H+-ATPase on apical membranes of an overwhelming numbers of cyst epithelial cells in all models of TSC, including the human kidney cysts. In contrast, kidney cysts in Pkd1 mutant mice showed no apical ClC-5 expression and very few H+-ATPase expressing cells.


These are the first reports on apical membrane localization of CLC-5 in A-intercalated cells in any disease state, and suggest that similar to late endosomes/lysosomes, CLC-5 and H+-ATPase may function synergistically on cyst epithelia by secreting Cl- and H+ into the cyst lumen. These results strongly point to enhanced translocation of CLC-5 and H+-ATPase from late endosomes/lysosomes to the apical membrane of cyst epithelia in TSC.


  • Veterans Affairs Support