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Gerrits, Tessa; Dijkstra, Kyra L.; Bruijn, Jan Anthonie; Scharpfenecker, Marion; Bijkerk, Roel; Baelde, Hans J.
Biochimica et biophysica acta. Molecular basis of disease, June 2024, 2024-Jun, 2024-06-00, 20240601, Volume: 1870, Issue: 5Journal Article
TGF-β is considered an important cytokine in the development of interstitial fibrosis in chronic kidney disease. The TGF-β co-receptor endoglin (ENG) tends to be upregulated in kidney fibrosis. ENG has two membrane bound isoforms generated via alternative splicing. Long-ENG was shown to enhance the extent of renal fibrosis in an unilateral ureteral obstruction mouse model, while short-ENG inhibited renal fibrosis. Here we aimed to achieve terminal intron retention of endoglin using antisense-oligo nucleotides (ASOs), thereby shifting the ratio towards short-ENG to inhibit the TGF-β1-mediated pro-fibrotic response. We isolated mRNA from kidney biopsies of patients with chronic allograft disease (CAD) (n = 12) and measured total ENG and short-ENG mRNA levels. ENG mRNA was upregulated 2.3 fold (p < 0.05) in kidneys of CAD patients compared to controls, while the percentage short-ENG of the total ENG mRNA was significantly lower (1.8 fold; p < 0.05). Transfection of ASOs that target splicing regulatory sites of ENG into TK173 fibroblasts led to higher levels of short-ENG (2 fold; p < 0.05). In addition, we stimulated these cells with TGF-β1 and measured a decrease in upregulation of ACTA2, COL1A1 and FN1 mRNA levels, and protein expression of αSMA, collagen type I, and fibronectin. These results show a potential for ENG ASOs as a therapy to reduce interstitial fibrosis in CKD. Display omitted •ASOs designed against the terminal intron of endoglin can alter isoform splicing.•Long-endoglin is a pro-fibrotic co-receptor in fibrotic kidney disease.•Short-endoglin reduces the TGF-β1-mediated pro-fibrotic response in fibroblasts.
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