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.

doi:10.1101/2025.01.14.632910

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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

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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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