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      CLCN5 5’UTR isoforms in human kidneys: differential expression analysis between controls and patients with glomerulonephritis

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          Abstract

          ClC-5, the electrogenic chloride/proton exchanger strongly expressed in renal proximal tubules, belongs to the endocytic macromolecular complex responsible for albumin and low-molecular-weight protein uptake. ClC-5 was found to be overexpressed in glomeruli of glomerulonephritis and in cultured human podocytes under albumin overload. The transcriptional regulation of human ClC-5 is not fully understood. Three functional promoters of various strengths and 11 different 5’ untranslated region (5’UTR) isoforms of CLCN5 messenger RNA (mRNA) were detected in the human kidney (variants 1–11). The aim of this study was to investigate the expression pattern of CLCN5 5’UTR variants and the CLCN5 common translated region in glomerulonephritis. The 5’UTR ends and the translated region of CLCN5 mRNA were analyzed using quantitative relative real-time PCR or quantitative comparative endpoint PCR with GAPDH as housekeeping gene in 8 normal kidneys and 12 renal biopsies from patients with glomerulonephritis. The expression profile for all variants in normal and glomerulonephritis biopsies was similar, and variant 3 and alternative variant 4 were the most abundantly expressed in both sets. In glomerulonephritis biopsies, isoforms under the control of a weak promoter (variants 4, 6 and 7) showed an increased expression leading to an increase in the CLCN5 translated region, underscoring their importance in kidney pathophysiology. Since weak promoters can be turned on by different stimuli, these data support the hypothesis that proteinuria could be one of the stimuli capable of starting a signaling pathway that induces an increase in CLCN5 transcription.

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          Author and article information

          Journal
          9501229
          8614
          J Investig Med
          J. Investig. Med.
          Journal of investigative medicine : the official publication of the American Federation for Clinical Research
          1081-5589
          1708-8267
          16 July 2020
          03 February 2020
          April 2020
          04 August 2020
          : 68
          : 4
          : 864-869
          Affiliations
          Kidney Histomorphology and Molecular Biology Laboratory, Clinical Nephrology Unit, Department of Medicine-DIMED, University of Padua, Padua, Italy
          Author notes

          Contributors FA and ET conceived the study. MC, LG and ET conducted the experiments. MC, LG and FA designed the experiments. LG, MC and DDP analyzed the data. GP provided assistance with the experimental methodology. MC, LG, FA and DDP wrote the manuscript. All authors approved the manuscript.

          Correspondence to: Dr Monica Ceol, Department of Medicine-DIMED, University of Padua, Padua 35129, Italy; monica.ceol@ 123456unipd.it
          Author information
          http://orcid.org/0000-0001-7489-2433
          http://orcid.org/0000-0001-9327-397X
          http://orcid.org/0000-0002-1870-4466
          http://orcid.org/0000-0003-2141-3472
          http://orcid.org/0000-0003-1534-4458
          Article
          PMC7402611 PMC7402611 7402611 nihpa1610362
          10.1136/jim-2019-001205
          7402611
          32019767
          09bdb97e-9556-4ec2-ba3f-d401abd65369
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