Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy

Alex Xianghua Zhou; Marie Jeansson; Liqun He; Leif Wigge; Pernilla Tonelius; Ramesh Tati; Linda Cederblad; Lars Muhl; Martin Uhrbom; Jianping Liu; Anna Björnson Granqvist; Lilach O. Lerman; Christer Betsholtz; Pernille B. Laerkegaard Hansen

doi:10.20944/preprints202403.1481.v1

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preprints.org > biology and life sciences > life sciences > doi: 10.20944/preprints202403.1481.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy

Anna Björnson Granqvist

Lilach O. Lerman

Christer Betsholtz

Pernille B. Laerkegaard Hansen

Version 1 : Received: 25 March 2024 / Approved: 25 March 2024 / Online: 25 March 2024 (11:38:53 CET)

A peer-reviewed article of this Preprint also exists.

Zhou, A.-X.; Jeansson, M.; He, L.; Wigge, L.; Tonelius, P.; Tati, R.; Cederblad, L.; Muhl, L.; Uhrbom, M.; Liu, J.; Björnson Granqvist, A.; Lerman, L.O.; Betsholtz, C.; Hansen, P.B.L. Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy. Int. J. Mol. Sci. 2024, 25, 4320. Zhou, A.-X.; Jeansson, M.; He, L.; Wigge, L.; Tonelius, P.; Tati, R.; Cederblad, L.; Muhl, L.; Uhrbom, M.; Liu, J.; Björnson Granqvist, A.; Lerman, L.O.; Betsholtz, C.; Hansen, P.B.L. Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy. Int. J. Mol. Sci. 2024, 25, 4320.

Abstract

Endothelial cell (EC) injury is a crucial contributor to progression of diabetic kidney disease (DKD), but the specific EC populations and mechanisms involved remain elusive. Kidney ECs (n=5,464) were collected at 3 timepoints from diabetic BTBRob/ob mice and non-diabetic littermates. Their heterogeneity, transcriptional changes, and alternative splicing during DKD progression were mapped using SmartSeq2 single-cell RNA sequencing (scRNAseq) and elucidated by pathway, network, and gene ontology enrichment analyses. We identified 13 distinct transcriptional EC phenotypes corresponding to different kidney vessel subtypes, confirmed by in-situ hybridization and immunofluorescence. EC subtypes along nephrons displayed extensive zonation related to their functions. Differential gene expression analyses in peritubular and glomerular EC in DKD underlined regulation of DKD-relevant pathways including EIF2 signaling, oxidative phosphorylation, and IGF1 signaling. Importantly, it revealed differential alteration of these pathways between the two EC subtypes and changes during disease progression. Furthermore, glomerular and peritubular EC also displayed aberrant and dynamic alteration of al-ternative splicing (AS), strongly associated with DNA repair. Strikingly, genes displaying differential transcription or alternative splicing participate in divergent biological processes. Our study reveals spatiotemporal regulation of gene transcription and AS linked to DKD progression, providing insight into pathomechanisms and clues to novel therapeutic targets for DKD treatment.

Keywords

diabetic nephropathy; transcriptomics; endothelium

Subject

Biology and Life Sciences, Life Sciences

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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