title: The Cap1-claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation.
abstract: The paracellular pathway through the tight junction provides an important route for transepithelial chloride reabsorption in the kidney, which regulates extracellular salt content and blood pressure. Defects in paracellular chloride reabsorption may in theory cause deregulation of blood pressure. However, there is no evidence to prove this theory or to demonstrate the in vivo role of the paracellular pathway in renal chloride handling. Here, using a tissue-specific KO approach, we have revealed a chloride transport pathway in the kidney that requires the tight junction molecule claudin-4. The collecting duct-specific claudin-4 KO animals developed hypotension, hypochloremia, and metabolic alkalosis due to profound renal wasting of chloride. The claudin-4-mediated chloride conductance can be regulated endogenously by a protease-channel-activating protease 1 (cap1). Mechanistically, cap1 regulates claudin-4 intercellular interaction and membrane stability. A putative cap1 cleavage site has been identified in the second extracellular loop of claudin-4, mutation of which abolished its regulation by cap1. The cap1 effects on paracellular chloride permeation can be extended to other proteases such as trypsin, suggesting a general mechanism may also exist for proteases to regulate the tight junction permeabilities. Together, we have discovered a theory that paracellular chloride permeability is physiologically regulated and essential to renal salt homeostasis and blood pressure control.
authors.affiliation: Department of Internal Medicine-Renal Division, Center for Investigation of Membrane Excitability Diseases, and Department of Physiology, Binzhou Medical College, Yantai 264003, China;
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112; and.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine-Renal Division, Center for Investigation of Membrane Excitability Diseases, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Neurology, Washington University Medical School, St Louis, MO 63110;
authors.forename: Ernie
authors.initials: E
authors.lastname: Gonzales
authors.affiliation: Department of Neurology, Washington University Medical School, St Louis, MO 63110;
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Perez
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Mingli
authors.initials: M
authors.lastname: Hou
authors.affiliation: Department of Internal Medicine-Renal Division.
authors.forename: Piyush
authors.initials: P
authors.lastname: Tripathi
authors.affiliation: Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112; and.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Hering-Smith
authors.affiliation: Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112; and jhou@wustl.edu lhamm@tulane.edu.
authors.forename: L Lee
authors.initials: LL
authors.lastname: Hamm
authors.affiliation: Department of Internal Medicine-Renal Division, Center for Investigation of Membrane Excitability Diseases, and jhou@wustl.edu lhamm@tulane.edu.
authors.forename: Jianghui
authors.initials: J
authors.lastname: Hou
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism*; D062506:Claudin-4 / Q000378:metabolism*; D004573:Electrolytes / Q000097:blood / Q000652:urine; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D018345:Mice, Knockout; D009928:Organ Specificity / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D065608:Renal Reabsorption / Q000187:drug effects; D012697:Serine Endopeptidases / Q000378:metabolism*; D013686:Telemetry; D014357:Trypsin / Q000378:metabolism; D000099271:Prostasin
chemical_list: D002712:Chlorides; D062506:Claudin-4; D004573:Electrolytes; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D014357:Trypsin; D000099271:Prostasin
keywords: chloride channel; epithelium; hypertension