Fig 1: GCSi treatment impacts HER signaling cascade in kidney macrophages.a–c Differentially expressed genes following GCSi treatment in the monocyte-macrophage population of (a) Col4a3 KO, (b) Nek8jck, and (c) Nphs2 cKO models. Down-regulated genes are highlighted in blue, and Upregulated genes are highlighted in red. Top 50 up- and downregulated genes are listed in supplementary data 7. d Proportion of cell clusters within the monocyte-macrophage lineage in Nek8jck and Col4a3 KO models. e, i Erbb4 expression profile and (e, ii) enrichment score analysis of HER signaling within this lineage. The box plots denote median, maximum, and minimum. Ranking of HER enrichment score is displayed as high (hi) and low (lo). f MSigDB hallmark pathways that are associated with (i) HERhi and (ii) HERlo monocyte-macrophage lineage clusters in Nek8jck model. g The expression levels of HER signaling-related genes in each kidney cell type identified in the Nek8jck model. HER receptors: Egfr, Erbb2, Erbb3, and Erbb4. HER ligands: Areg, Btc, Egf, Ereg, HbEgf, Nrg1, Nrg2, Nrg3, Nrg4, and Tgfα. Areg Amphiregulin, Btc Betacellulin, Egf Epidermal growth factor, Ereg epiregulin, HbEgf Heparin-binding EGF-like growth factor, Nrg Neuregulin and Tgfα Transforming growth factor alpha. EMT epithelial to mesenchymal transition. pct_express percent expressing.
Fig 2: GCSi treatment has a divergent effect on metabolic reliance in non-inflammatory and inflammatory-induced BM macrophages.a The ratio of OCR to ECAR was determined in wild-type BM macrophages in vitro under different conditions (n ≥ 3). b IL6 secretion in LPS-induced wildtype BM macrophages following GCSi treatment and subsequent BTC stimulation (n = 5). Results are from at least 3 independent experiments. c PCA plot of the WT BM macrophages sequencing data. Depicted are replicates of each condition: GCSi treated groups under LPS stimulated condition and GCSi treated groups under basal condition. Common genes mediated by LPS in wild-type BM macrophages that are shared across all the groups (each group has at least 3 independent biological replicates). d, i Venn diagram of the differentially expressed genes mediated by Eliglustat, GCSi 1 or GCSi 2 in LPS stimulated WT BM macrophages and (ii) the heatmap representing the overlap gene signatures between the LPS DEGs (LPS-stimulated vehicle group vs unstimulated vehicle group) and GCSi mediated signatures (log2 fold-change: 0.585; adjusted p value < 0.05). d, iii Cellular functions regulated by Eliglustat, GCSi 1, and GCSi 2 in LPS-stimulated WT BM macrophages. Data are expressed as mean ± standard deviation. a, b Two-way ANOVA was performed for statistical analysis.
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