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Renal deletion of LRRC8/VRAC channels induces proximal tubulopathy

Item Type:Article
Title:Renal deletion of LRRC8/VRAC channels induces proximal tubulopathy
Creators Name:López-Cayuqueo, K.I. and Planells-Cases, R. and Pietzke, M. and Oliveras, A. and Kempa, S. and Bachmann, S. and Jentsch, T.J.
Abstract:BACKGROUND: Volume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these swelling-activated channels conduct chloride, amino acids, organic osmolytes, and drugs. Despite VRACs' role in cell volume regulation, and large osmolarity changes in the kidney, neither the localization nor the function of VRACs in the kidney is known. METHODS: Mice expressing epitope-tagged LRRC8 subunits were used to determine the renal localization of all VRAC subunits. Mice carrying constitutive deletions of Lrrc8b-e, or with inducible or cell-specific ablation of Lrrc8a, were analyzed to assess renal functions of VRACs. Analysis included histology, urine and serum parameters in different diuresis states, and metabolomics. RESULTS: The kidney expresses all five VRAC subunits with strikingly distinct localization. Whereas LRRC8C is exclusively found in vascular endothelium, all other subunits are found in the nephron. LRRC8E is specific for intercalated cells, whereas LRRC8A, LRRC8B, and LRRC8D are prominent in basolateral membranes of proximal tubules. Conditional deletion of LRRC8A in proximal but not distal tubules and constitutive deletion of LRRC8D cause proximal tubular injury, increased diuresis, and mild Fanconi-like symptoms. CONCLUSIONS: VRAC/LRRC8 channels are crucial for the function and integrity of proximal tubules, but not for more distal nephron segments in spite of their larger need for volume regulation. LRRC8A/D channels may be required for the basolateral exit of many organic compounds, including cellular metabolites, in proximal tubules. Proximal tubular injury likely results from combined accumulation of several transported molecules in the absence of VRAC channels.
Keywords:VSOR, RVD, Transepithelial, Glycosuria, Chloride Channel, Cl(-) Channel, Lysosome, Fanconi-Like Syndrome, Animals, Mice
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
Page Range:1528-1545
Date:August 2022
Additional Information:Copyright © 2022 by the American Society of Nephrology.
Official Publication:https://doi.org/10.1681/ASN.2021111458
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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