Cell Type–Specific Expression of Long Noncoding RNAs in Human Diabetic Kidneys Identifies TARID as a Key Regulator of Podocyte Function
Diabetes, vol. 74, pp. 2075–2088
Abstract
Long noncoding RNAs (lncRNAs) play essential roles in cellular processes, often exhibiting cell type-specific expression and influencing kidney function. While single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cellular specificity, past studies focus solely on protein-coding genes. We hypothesize that lncRNAs, due to their cell-specific nature, have crucial functions within particular renal cells and thereby play essential roles in renal cell function and disease. Using single-nucleus RNA-seq (snRNA-seq) data from kidney samples of five healthy individuals and six patients with diabetic kidney disease (DKD), we explored the noncoding transcriptome. Cell type-specific lncRNAs were identified, and their differential expression in DKD was assessed. Integrative analyses included expression quantitative trait loci (eQTL), genome-wide association studies (GWAS) for estimated glomerular filtration rate (eGFR), and gene regulatory networks. Functional studies focused on TCF21 antisense RNA inducing promoter demethylation (TARID), a lncRNA with podocyte-specific expression, to elucidate its role in podocyte health. We identified 174 lncRNAs with cell type-specific expression across kidney cell types. Of these, 54 lncRNAs were differentially expressed in DKD. Integrative analyses, including eQTL data, GWAS results for eGFR, and gene regulatory networks, pinpointed TARID, a podocyte-specific lncRNA, as a key candidate upregulated in DKD. Functional studies confirmed TARID's podocyte-specific expression and revealed its central role in actin cytoskeleton reorganization. Our study provides a comprehensive resource of single-cell lncRNA expression in the human kidney and highlights the importance of cell type-specific lncRNAs in kidney function and disease. Specifically, we demonstrate the functional relevance of TARID in podocyte health. ARTICLE HIGHLIGHTS: This study provides a resource for kidney (cell type-specific) long noncoding (lnc)RNA expression and demonstrates the importance of lncRNAs in renal health. We identified 174 cell type-specific lncRNAs in the human kidney, with 54 showing altered expression in diabetic kidney disease. TCF21 antisense RNA inducing promoter demethylation (TARID), a podocyte-specific lncRNA upregulated in diabetic kidney disease, is crucial for actin cytoskeleton reorganization in podocytes.
Authors 20
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Juliette A. de Klerk Aachen Department of Cell and Chemical Biology Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 2Department of Cell and Chemical Biology
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2 , the Netherlands
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
2Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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Roderick C. Slieker Aachen Department of Cell and Chemical Biology 2Department of Cell and Chemical Biology
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2 , the Netherlands
2Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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Washington University in St. Louis
Affiliation as printed
Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis 3 , St. Louis, MO
3Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO
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Washington University in St. Louis
Affiliation as printed
Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis 3 , St. Louis, MO
3Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO
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Rudmer J. Postma Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Leen M. ‘t Hart Aachen Department of Cell and Chemical Biology 2Department of Cell and Chemical Biology
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2 , the Netherlands
2Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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Janneke H D Peerlings Aachen Department of Cell and Chemical Biology 2Department of Cell and Chemical Biology
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2 , the Netherlands
2Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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Floris Herrewijnen Aachen Department of Cell and Chemical Biology 2Department of Cell and Chemical Biology
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2 , the Netherlands
2Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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Heein Song Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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H. Siebe Spijker Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Sébastien J. Dumas Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 4The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW)
Leiden University · Leiden University Medical Center · Novo Nordisk Foundation Center for Stem Cell Medicine
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center 4 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
4The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, the Netherlands
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Marije Koning Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Loïs A.K. van der Pluijm Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center 5 , Leiden, the Netherlands
5Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center 5 , Leiden, the Netherlands
5Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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Joris I. Rotmans Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Anton Jan van Zonneveld Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Cardiovascular Research Center, Department of Medicine, New York University Grossman School of Medicine 6 , New York, NY
6Cardiovascular Research Center, Department of Medicine, New York University Grossman School of Medicine, New York, NY
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Washington University in St. Louis
Affiliation as printed
Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis 3 , St. Louis, MO
3Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO
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Roel Bijkerk corresponding Aachen Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine 1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine
Leiden University · Leiden University Medical Center
Affiliation as printed
Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center 1 , Leiden, the Netherlands
1Division of Nephrology and the Einthoven Laboratory for Vascular and Regenerative Medicine. Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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