Single-Nucleus RNA Sequencing Reveals Loss of Distal Convoluted Tubule 1 Renal Tubules in HIV Viral Protein R Transgenic Mice

Khun Zaw Latt, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: khunzaw.latt@nih.gov.
Teruhiko Yoshida, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Shashi Shrivastav, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Amin Abedini, Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Jeff M. Reece, Advanced Light Microscopy & Image Analysis Core (ALMIAC), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Zeguo Sun, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Hewang Lee, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC.
Koji Okamoto, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Hospital, Aoba-ku, Sendai, Miyagi, Japan.
Pradeep Dagur, Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Yu Ishimoto, Polycystic Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Jurgen Heymann, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Yongmei Zhao, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick, Maryland.
Joon-Yong Chung, Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Stephen Hewitt, Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Pedro A. Jose, Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC; Departments of Physiology and Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington, DC.
Kyung Lee, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
John Cijiang He, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Cheryl A. Winkler, Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute and Basic Research Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Mark A. Knepper, Epithelial Systems Biology Laboratory, Systems Biology Center, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Tomoshige Kino, Laboratory for Molecular and Genomic Endocrinology, Division of Translational Medicine, Sidra Medicine, Doha, Qatar.
Avi Z. Rosenberg, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Katalin Susztak, Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Jeffrey B. Kopp, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: jeffreyk@intra.niddk.nih.gov.

Document Type

Journal Article

Publication Date

7-18-2024

Journal

The American journal of pathology

DOI

10.1016/j.ajpath.2024.06.006

Abstract

Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice. The results show that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05); in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT mice (P < 0.01). Immunohistochemistry revealed fewer Slc12a3Pvalb DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT samples in the DCT cluster showed down-regulation of the Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 down-regulation in DCT1 cells and loss of Slc12a3Pvalb DCT1 segments.

Department

Medicine

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