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bioRxiv · 10.1101/2025.01.14.632910

Cell Type-Specific and Diabetic Kidney Disease-Associated Expression of Long Non-Coding RNAs in Human Kidneys

de Klerk, J. A.·Slieker, R.·Parker, W.·Wu, H.·Muto, Y.·Postma, R. J.·'t Hart, L. M.·Peerlings, J. H. D.·Herrewijnen, F. J.·Song, H. I.·Spijker, S. H.·Dumas, S. J.·Koning, M.·van der Pluijm, L. A. K.·Baelde, H. J. J.·Gerrits, T.·Rotmans, J. I.·van Zonneveld, A. J.·van Solingen, C.·Humphreys, B.·Bijkerk, R.
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Abstract

BackgroundLong non-coding 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. MethodsUsing single-nucleus RNA sequencing (snRNA-seq) data from kidney samples of five healthy individuals and six DKD patients, we explored the non-coding 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 TARID, a lncRNA with podocyte-specific expression, to elucidate its role in podocyte health. Resultswe identified 349 lncRNAs with cell type-specific expression across kidney cell types. Of these, 104 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 TARIDs podocyte-specific expression and revealed its central role in actin cytoskeleton reorganization, a critical process in podocyte health. ConclusionsOur 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. This work underscores the utility of integrating scRNA-seq with functional genomics to uncover novel regulatory mechanisms in kidney biology. Key pointsO_LIThis provides a resource for kidney (cell type-specific) lncRNA expression and demonstrates the importance of lncRNAs in renal health. C_LIO_LIWe identified 349 cell type-specific lncRNAs in the human kidney, with 104 showing altered expression in diabetic kidney disease (DKD). C_LIO_LITARID, a podocyte-specific lncRNA upregulated in DKD, is crucial for actin cytoskeleton reorganization in podocytes. C_LI

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de Klerk, J. A., Slieker, R., Parker, W., Wu, H., Muto, Y., Postma, R. J., 't Hart, L. M., Peerlings, J. H. D., Herrewijnen, F. J., Song, H. I., Spijker, S. H., Dumas, S. J., Koning, M., van der Pluijm, L. A. K., Baelde, H. J. J., Gerrits, T., Rotmans, J. I., van Zonneveld, A. J., van Solingen, C., Humphreys, B., Bijkerk, R.. 2025-01-18. Cell Type-Specific and Diabetic Kidney Disease-Associated Expression of Long Non-Coding RNAs in Human Kidneys. https://doi.org/10.1101/2025.01.14.632910

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