Targeting long non-coding RNA MALAT1 preserves endothelial cell integrity and protects against kidney fibrosis

Zhao, Q.; Pluijm, L.A.K. van der; Gourvest, M.; Lafzi, A.; Peled, D.; Rubin, W.G.; ... ; Bijkerk, R. (2025)

Article / Letter to editor

Loss of integrity of the capillary network is directly associated with the development of kidney fibrosis resulting in chronic kidney disease. Here, we characterized long non-coding RNAs (lncRNAs) in endothelial cells (ECs) during the development of kidney fibrosis. Using a murine EC lineage-tracing model, we observed expression of the conserved lncRNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1) to be elevated in ECs upon kidney injury; either by ischemia-reperfusion injury or by unilateral ureteral obstruction (UUO). In addition, we found elevated MALAT1 expression in the kidney and circulation of patients with fibrotic kidney diseases. Pharmacological intervention of Malat1 initiated protection against fibrosis in the UUO model, illustrated by a marked decline in collagen deposition and a concomitant decrease in interstitial alpha-smooth muscle actin (alpha-SMA)-positive cells in the kidney. This protective effect was further highlighted by an increase in capillary density and reduced endothelial-to-mesenchymal transition. Mechanistically, transcriptomic analyses of kidney ECs upon Malat1 knockdown demonstrated increased EC-matrix-receptor interaction. Furthermore, we show that silencing of MALAT1 results in increased barrier function and angiogenic response, less vascular leakage, and decreased focal adhesions. Finally, integration with in silico analyses and RNA immunoprecipitation confirmed binding of MALAT1 to SUZ12, a member of the PRC2 complex, suggesting a transcriptional regulatory role for MALAT1. Collectively, our findings classify the lncRNA MALAT1 as an important regulator of EC function and kidney health. As such, targeting MALAT1 may provide novel strategies to reduce kidney fibrosis.

• All authors: Zhao, Q.; Pluijm, L.A.K. van der; Gourvest, M.; Lafzi, A.; Peled, D.; Rubin, W.G.; Klerk, J.A. de; Slieker, R.C.; Hart, L.M.T.; Stam, W.; Oeveren-Rietdijk, A.M. van; Duijs, J.M.G.J.; Koudijs, A.; Rotmans, J.I.; Kazan, H.; Zonneveld, A.J. van; Solingen, C. van; Bijkerk, R.
• Date: 2025-09-09
• Journal: Molecular Therapy: Nucleic Acids
• Volume: 36
• Issue: 3
• DOI: doi:10.1016/j.omtn.2025.102689