Universität zu Köln

Filipów, Samantha ORCID: 0000-0002-9290-1273 (2025). The role of Wt1os lncRNA in the pathogenesis of focal segmental glomerulosclerosis (FSGS) and podocyte biology. PhD thesis, Universität zu Köln.

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Abstract

LncRNAs (long non-coding RNAs) are a diverse class of regulatory RNAs that influence gene expression by modulating chromatin activity, transcription, RNA splicing, and translation. Their dysregulation has been implicated in various human diseases, including cancer, neurological disorders, and kidney diseases. Previous studies have shown that the lncRNA Tug1 (taurine up-regulated gene 1) protects against podocyte loss by regulating PPARy (peroxisome proliferator–activated receptors) and mitochondrial function, while LOC105374325 overexpression induces an FSGS-like phenotype in mice. However, in general, studies on lncRNAs in the glomerulus remain limited, and their role in podocyte biology is largely unexplored. Using RNAseq, we identified 241 lncRNAs associated with FSGS in mouse models, including Wt1os, an lncRNA which was significantly downregulated in several of the models. Wt1os is transcribed from a bidirectional promoter shared with Wt1, a gene encoding for a transcription factor essential for podocyte biology. Wt1os is conserved with its human orthologue, WT1-AS, in a syntenic manner. WT1-AS has been implicated in cancer biology, where it appears to regulate tumor growth, metastasis, and invasion. However, the role of Wt1os/WT1-AS in kidney physiology, FSGS and podocyte biology remains elusive. Here, we shown that loss of Wt1os in mice led to podocyte foot process effacement and proteinuria. Transcriptomic analysis of glomeruli from Wt1os-deficient mice revealed significant gene expression changes. Gain-of-function experiments in cultured mouse podocytes, demonstrated that Wt1os localizes to the nucleus, has pro-migratory effect and regulated calcium signaling in a Rgs1-dependent manner. Using human podocyte cells, we confirmed the conserved nuclear localization of WT1-AS and, through loss-of-function experiments, demonstrated its crucial role in cell viability. RGS1 is consistently downregulated upon loss of Wt1os across all cell culture models and in the mouse line, implicating its potential role as a downstream mediator of Wt1os in podocytes. Our findings highlight Wt1os as a novel regulator of podocyte biology, making a substantial contribution to the limited knowledge on lncRNAs with a clear-cut implication in glomerular pathophysiology.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Filipów, Samantha samantha.filipow@uk-koeln.de orcid.org/0000-0002-9290-1273 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-788929
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Innere Medizin > Klinik II für Innere Medizin - Nephrologie, Rheumatologie, Diabetologie und Allgemeine Innere Medizin
Subjects:	Life sciences Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language podocytes English lncRNA English FSGS English
Date of oral exam:	16 June 2025
Referee:	Name Academic Title Mueller, Roman-Ulrich Prof. Dr. med. Gehring, Niels Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78892