The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation
| Autor: | L. Lee Hamm, Jing Yang, Ronaldo Perez, Yongfeng Gong, Kathleen S. Hering-Smith, Miao Yu, Mingli Hou, Jianghui Hou, Piyush Tripathi, Ernie Gonzales |
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| Rok vydání: | 2014 |
| Předmět: |
Cell Membrane Permeability
Blood Pressure Biology Kidney digestive system Renal chloride reabsorption Electrolytes Chlorides medicine Animals Humans Telemetry Trypsin Claudin-4 Kidney Tubules Collecting Claudin Mice Knockout Multidisciplinary urogenital system Reabsorption Cell Membrane Serine Endopeptidases Renal Reabsorption Kidney metabolism Recombinant Proteins Cell biology Protein Transport HEK293 Cells medicine.anatomical_structure PNAS Plus Biochemistry Organ Specificity Paracellular transport Chloride channel RNA Interference Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences. 111 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1406741111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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