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GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation.

Authors
  • Hinze, Christian1, 2, 3
  • Ruffert, Janett1, 4
  • Walentin, Katharina1
  • Himmerkus, Nina5
  • Nikpey, Elham6, 7
  • Tenstad, Olav6
  • Wiig, Helge6
  • Mutig, Kerim8
  • Yurtdas, Zeliha Yesim1, 4
  • Klein, Janet D9
  • Sands, Jeff M9
  • Branchi, Federica10
  • Schumann, Michael10
  • Bachmann, Sebastian8
  • Bleich, Markus5
  • Schmidt-Ott, Kai M11, 3
  • 1 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. , (Germany)
  • 2 Berlin Institute of Health, Berlin, Germany. , (Germany)
  • 3 Departments of Nephrology and Medical Intensive Care.
  • 4 Berlin Institute of Urologic Research, Berlin, Germany. , (Germany)
  • 5 Institute of Physiology, Christian Albrechts University Kiel, Kiel, Germany. , (Germany)
  • 6 Department of Biomedicine, University of Bergen, Bergen, Norway. , (Norway)
  • 7 Department of Medicine, Haukeland University Hospital, Bergen, Norway; and. , (Norway)
  • 8 Anatomy, and.
  • 9 Renal Division, Department of Medicine, Emory University, Atlanta, Georgia. , (Georgia)
  • 10 Gastroenterology, Infectious Diseases and Rheumatology, Charité Universitätsmedizin, Berlin, Germany. , (Germany)
  • 11 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; [email protected] , (Germany)
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology
Publication Date
Mar 01, 2018
Volume
29
Issue
3
Pages
857–868
Identifiers
DOI: 10.1681/ASN.2017030353
PMID: 29237740
Source
Medline
Keywords
License
Unknown

Abstract

Collecting ducts make up the distal-most tubular segments of the kidney, extending from the cortex, where they connect to the nephron proper, into the medulla, where they release urine into the renal pelvis. During water deprivation, body water preservation is ensured by the selective transepithelial reabsorption of water into the hypertonic medullary interstitium mediated by collecting ducts. The collecting duct epithelium forms tight junctions composed of barrier-enforcing claudins and exhibits a higher transepithelial resistance than other segments of the renal tubule exhibit. However, the functional relevance of this strong collecting duct epithelial barrier is unresolved. Here, we report that collecting duct-specific deletion of an epithelial transcription factor, grainyhead-like 2 (GRHL2), in mice led to reduced expression of tight junction-associated barrier components, reduced collecting duct transepithelial resistance, and defective renal medullary accumulation of sodium and other osmolytes. In vitro, Grhl2-deficient collecting duct cells displayed increased paracellular flux of sodium, chloride, and urea. Consistent with these effects, Grhl2-deficient mice had diabetes insipidus, produced dilute urine, and failed to adequately concentrate their urine after water restriction, resulting in susceptibility to prerenal azotemia. These data indicate a direct functional link between collecting duct epithelial barrier characteristics, which appear to prevent leakage of interstitial osmolytes into urine, and body water homeostasis.

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