| First Author | Gong Y | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 14 | Pages | 4340-5 |
| PubMed ID | 25831548 | Mgi Jnum | J:220813 |
| Mgi Id | MGI:5636521 | Doi | 10.1073/pnas.1421441112 |
| Citation | Gong Y, et al. (2015) KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8. Proc Natl Acad Sci U S A 112(14):4340-5 |
| abstractText | A rare Mendelian syndrome-pseudohypoaldosteronism type II (PHA-II)-features hypertension, hyperkalemia, and metabolic acidosis. Genetic linkage studies and exome sequencing have identified four genes-with no lysine kinase 1 (wnk1), wnk4, Kelch-like 3 (KLHL3), and Cullin 3 (Cul3)-mutations of which all caused PHA-II phenotypes. The previous hypothesis was that the KLHL3-Cul3 ubiquitin complex acted on the wnk4-wnk1 kinase complex to regulate Na(+)/Cl(-) cotransporter (NCC) mediated salt reabsorption in the distal tubules of the kidney. Here, we report the identification of claudin-8 as a previously unidentified physiologic target for KLHL3 and provide an alternative explanation for the collecting duct's role in PHA-II. Using a tissue-specific KO approach, we have found that deletion of claudin-8 in the collecting duct of mouse kidney caused hypotension, hypokalemia, and metabolic alkalosis, an exact mirror image of PHA-II. Mechanistically, the phenotypes in claudin-8 KO animals were caused by disruption of the claudin-8 interaction with claudin-4, the paracellular chloride channel, and delocalization of claudin-4 from the tight junction. In mouse collecting duct cells, knockdown of KLHL3 profoundly increased the paracellular chloride permeability. Mechanistically, KLHL3 was directly bound to claudin-8, and this binding led to the ubiquitination and degradation of claudin-8. The dominant PHA-II mutation in KLHL3 impaired claudin-8 binding, ubiquitination, and degradation. These findings have attested to the concept that the paracellular pathway is physiologically regulated through the ubiquitination pathway, and its deregulation may lead to diseases of electrolyte and blood pressure imbalances. |
