In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 9 ( 2022-9-21), p. e0273313-
Abstract:
HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has drawn increased attention because sodium wasting is common in hospitalized HIV/AIDS patients. We used viral protein R (Vpr)-transgenic mice to investigate the mechanisms whereby Vpr contributes to urinary sodium wasting. In phosphoenolpyruvate carboxykinase promoter-driven Vpr-transgenic mice, in situ hybridization showed that Vpr mRNA was expressed in all nephron segments, including the distal convoluted tubule. Vpr-transgenic mice, compared with wild-type littermates, markedly increased urinary sodium excretion, despite similar plasma renin activity and aldosterone levels. Kidneys from Vpr-transgenic mice also markedly reduced protein abundance of the Na + -Cl - cotransporter (NCC), while mineralocorticoid receptor (MR) protein expression level was unchanged. In African green monkey kidney cells, Vpr abrogated the aldosterone-mediated stimulation of MR transcriptional activity. Gene expression of Slc12a3 (NCC) in Vpr-transgenic mice was significantly lower compared with wild-type mice, assessed by both qRT-PCR and RNAScope in situ hybridization analysis. Chromatin immunoprecipitation assays identified multiple MR response elements (MRE), located from 5 kb upstream of the transcription start site and extending to the third exon of the SLC12A3 gene. Mutation of MRE and SP1 sites in the SLC12A3 promoter region abrogated the transcriptional responses to aldosterone and Vpr, indicating that functional MRE and SP1 are required for the SLC12A3 gene suppression in response to Vpr. Thus, Vpr attenuates MR transcriptional activity and inhibits Slc12a3 transcription in the distal convoluted tubule and contributes to salt wasting in Vpr-transgenic mice.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0273313
DOI:
10.1371/journal.pone.0273313.g001
DOI:
10.1371/journal.pone.0273313.g002
DOI:
10.1371/journal.pone.0273313.g003
DOI:
10.1371/journal.pone.0273313.g004
DOI:
10.1371/journal.pone.0273313.g005
DOI:
10.1371/journal.pone.0273313.g006
DOI:
10.1371/journal.pone.0273313.g007
DOI:
10.1371/journal.pone.0273313.s001
DOI:
10.1371/journal.pone.0273313.s002
DOI:
10.1371/journal.pone.0273313.s003
DOI:
10.1371/journal.pone.0273313.s004
DOI:
10.1371/journal.pone.0273313.s005
DOI:
10.1371/journal.pone.0273313.s006
DOI:
10.1371/journal.pone.0273313.s007
DOI:
10.1371/journal.pone.0273313.s008
DOI:
10.1371/journal.pone.0273313.s009
DOI:
10.1371/journal.pone.0273313.s010
DOI:
10.1371/journal.pone.0273313.r001
DOI:
10.1371/journal.pone.0273313.r002
DOI:
10.1371/journal.pone.0273313.r003
DOI:
10.1371/journal.pone.0273313.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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