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GRHL2 is required for collecting duct epithelial barrier function and renal osmoregulation

Item Type:Article
Title:GRHL2 is required for collecting duct epithelial barrier function and renal osmoregulation
Creators Name:Hinze, C. and Ruffert, J. and Walentin, K. and Himmerkus, N. and Nikpey, E. and Tenstad, O. and Wiig, H. and Mutig, K. and Yurtdas, Z.Y. and Klein, J.D. and Sands, J.M. and Branchi, F. and Schumann, M. and Bachmann, S. and Bleich, M. and Schmidt-Ott, K.M.
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.
Keywords:Epithelial Barrier Function, Renal Collecting Duct Epithelium, Urinary Concentration, Diabetes Insipidus, Prerenal Azotemia, Grainyhead-Like 2 Transcription Factor, Animals, Mice
Source:Journal of the American Society of Nephrology
ISSN:1046-6673
Publisher:American Society of Nephrology (U.S.A.)
Volume:29
Number:3
Page Range:857-868
Date:March 2018
Official Publication:https://doi.org/10.1681/ASN.2017030353
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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