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oai:uvadoc.uva.es:10324/662742025-09-05T11:48:01Zcom_10324_1134com_10324_931com_10324_894col_10324_1213
UVaDOC author Nakamura, Toshifumi author Bonnard, Benjamin author Palacios Ramírez, Roberto author Fernández-Celis, Amaya author Jaisser, Frédéric author López-Andrés, Natalia 2024-02-15T12:48:42Z 2024-02-15T12:48:42Z 2022 Int J Mol Sci. 2022 Jun 15 1422-0067 https://uvadoc.uva.es/handle/10324/66274 10.3390/ijms23126680 6680 12 International Journal of Molecular Sciences 23 1422-0067 The beneficial effects of mineralocorticoid receptor (MR) antagonists (MRAs) for various kidney diseases are established. However, the underlying mechanisms of kidney injury induced by MR activation remain to be elucidated. We recently reported aldosterone-induced enhancement of proteoglycan expression in mitral valve interstitial cells and its association with fibromyxomatous valvular disorder. As the expression of certain proteoglycans is elevated in several kidney diseases, we hypothesized that proteoglycans mediate kidney injury in the context of aldosterone/MR pathway activation. We evaluated the proteoglycan expression and tissue injury in the kidney and isolated glomeruli of uninephrectomy/aldosterone/salt (NAS) mice. The MRA eplerenone was administered to assess the role of the MR pathway. We investigated the direct effects of biglycan, one of the proteoglycans, on macrophages using isolated macrophages. The kidney samples from NAS-treated mice showed enhanced fibrosis and increased expression of biglycan accompanying glomerular macrophage infiltration and enhanced expression of TNF-α, iNOS, Nox2, CCL3 (C-C motif chemokine ligand 3), and phosphorylated NF-κB. Eplerenone blunted these changes. Purified biglycan stimulated macrophages to express TNF-α, iNOS, Nox2, and CCL3. This was prevented by a toll-like receptor 4 (TLR4) or NF-κB inhibitor, indicating that biglycan stimulation is dependent on the TLR4/NF-κB pathway. We identified the proteoglycan biglycan as a novel target of MR involved in MR-induced glomerular injury and macrophage infiltration via a biglycan/TLR4/NF-κB/CCL3 cascade eng Attribution-NonCommercial-NoDerivatives 4.0 Internacional Biglycan Is a Novel Mineralocorticoid Receptor Target Involved in Aldosterone/Salt-Induced Glomerular Injury info:eu-repo/semantics/article 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