Title

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

Authors

Shashi Shrivastav, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Hewang Lee, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Koji Okamoto, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Huiyan Lu, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Teruhiko Yoshida, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Khun Zaw Latt, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Hidefumi Wakashin, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
James L. Dalgleish, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Erik H. Koritzinsky, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.
Peng Xu, Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America.
Laureano D. Asico, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC, United States of America.
Joon-Yong Chung, Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, United States of America.
Stephen Hewitt, Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, United States of America.
John J. Gildea, Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America.
Robin A. Felder, Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America.
Pedro A. Jose, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC, United States of America.
Avi Z. Rosenberg, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
Mark A. Knepper, Epithelial Systems Biology Laboratory, Systems Biology Center, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland, United States of America.
Tomoshige Kino, Laboratory for Molecular and Genomic Endocrinology, Division of Translational Medicine, Sidra Medicine, Doha, Qatar.
Jeffrey B. Kopp, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland, United States of America.

Document Type

Journal Article

Publication Date

1-1-2022

Journal

PloS one

Volume

17

Issue

9

DOI

10.1371/journal.pone.0273313

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.

Department

Medicine

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