Extended Data Fig. 6: Liver senescence results in transcriptional changes in the renal proximal tubular cell compartment.

(a) Dot plot of pathways resulting from unsupervised GSEA of differentially expressed genes between ΔMdm2^Hep and control PTCs. Differential expression analysis was performed between ΔMdm2^Hep and control PTCs and the ranked gene set was used to perform unsupervised GSEA against Gene Ontology (GO) and KEGG pathways. The size of the dots represents the number of downregulated (suppressed, left) or upregulated (activated, right) genes in the ΔMdm2^Hep PTCs for each pathway (count) with colour representing statistical significance; Permutation test. (b) Representative images from a single batch of dual immunofluorescence staining for p21 and renal tubular epithelial markers (LRP2 or CALB1) on ΔMdm2^Hep kidneys at day 4; LRP2 is expressed on the apical brush boarder of the PTCs; n-5/6 for control/ ΔMdm2^Hep respectively. Scale bars are 50μm and 5μm in inset magnification. (c) UMAP plot showing the clusters of the cells (red versus grey) of the scRNA-seq data from analysis of 3 kidneys from control mice and 3 kidneys from ΔMdm2^Hep mice taken 4 days after induction highlighting cells with a positive score for the senescence signature (sen) from O’Sullivan et al.¹⁴. (d) UMAP plot of the same cells shown in panel c highlighting co-occurrence (yellow) of the p21 signatures (Fig. 3c) and the renal tubular senescence signature from O’Sullivan et al.¹. (e) Heatmap of relative expression of Slc transporter genes in the PTC compartment grouped by p21 signature score in each experimental condition; PTCs without the p21 signature in both conditions are merged as the left-hand column. Source numerical data are available in source data.