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      Loss of primary cilia increases polycystin-2 and TRPV4 and the appearance of a nonselective cation channel in the mouse cortical collecting duct

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          Abstract

          Flow-related bending of cilia results in Ca 2+ influx through a polycystin-1 (Pkd1) and polycystin-2 (Pkd2) complex, both of which are members of the transient receptor potential (TRP) family (TRPP1 and TRPP2, respectively). Deletion of this complex as well as cilia result in polycystic kidney disease. The Ca 2+ influx pathway has been previously characterized in immortalized collecting duct cells without cilia and found to be a 23-pS channel that was a multimere of TRPP2 and TRPV4. The purpose of the present study was to determine if this TRPP2 and TRPV4 multimere exists in vivo. Apical channel activity was measured using the patch-clamp technique from isolated split-open cortical collecting ducts from adult conditional knockout mice with ( Ift88 flox/flox ) or without ( Ift88 −/− ) cilia. Single tubules were isolated for measurements of mRNA for Pkd1, Pkd2, Trpv4, and epithelial Na + channel subunits. The predominant channel activity from Ift88 flox/flox mice was from epithelial Na + channel [5-pS Na +-selective channels with long mean open times (475.7 ± 83.26 ms) and open probability > 0.2]. With the loss of cilia, the predominant conductance was a 23-pS nonselective cation channel (reversal potential near 0) with a short mean open time (72 ± 17 ms), open probability < 0.08, and a characteristic flickery opening. Loss of cilia increased mRNA levels for Pkd2 and Trpv4 from single isolated cortical collecting ducts. In conclusion, 23-pS channels exist in vivo, and activity of this channel is elevated with loss of cilia, consistent with previous finding of an elevated-unregulated Ca 2+-permeable pathway at the apical membrane of collecting duct cells that lack cilia.

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          Author and article information

          Journal
          Am J Physiol Renal Physiol
          Am. J. Physiol. Renal Physiol
          ajprenal
          Am J Physiol Renal Physiol
          AJPRENAL
          American Journal of Physiology - Renal Physiology
          American Physiological Society (Bethesda, MD )
          1931-857X
          1522-1466
          1 September 2019
          17 July 2019
          1 September 2020
          : 317
          : 3
          : F632-F637
          Affiliations
          [1] 1Division of Nephrology, Department of Medicine, Medical University of South Carolina , Charleston, South Carolina
          [2] 2Division of Nephrology, Department of Medicine, Emory University , Atlanta, Georgia
          [3] 3Division of Nephrology, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama
          Author notes
          Address for reprint requests and other correspondence: T. Saigusa, Div. of Nephrology, Dept. of Medicine, Univ. of Alabama at Birmingham, 1720 2nd Ave. S., LHRB 621, Birmingham, AL 35294 (e-mail: tsaigusa@ 123456uabmc.edu ).
          Article
          PMC6766628 PMC6766628 6766628 F-00210-2019 F-00210-2019
          10.1152/ajprenal.00210.2019
          6766628
          31313950
          46323b07-d7a5-4fd8-95ad-6676e68f3ced
          Copyright © 2019 the American Physiological Society
          History
          : 29 April 2019
          : 10 July 2019
          : 11 July 2019
          Funding
          Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 10.13039/100000062
          Award ID: K08DK106465
          Award ID: P30DK074038
          Award ID: R03DK119717
          Award ID: R01DK110409
          Categories
          Rapid Report

          calcium channel,transient receptor potential,polycystic kidney disease,mechanosensor,ciliopathy

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