SR9009 attenuates TGF-β1-induced renal fibrotic responses by inhibiting the NOX4/p38 signaling pathway in NRK-49F cells.

Autor: Takaguri A; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan., Shinohe S; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan., Noro R; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan., Sakuraba M; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan., Satoh C; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan., Ohashi R; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan., Satoh K; Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine-ku, Sapporo, 006-8590, Japan. Electronic address: kumi@hus.ac.jp.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Dec 01; Vol. 987, pp. 177162. Date of Electronic Publication: 2024 Dec 01.
DOI: 10.1016/j.ejphar.2024.177162
Abstrakt: The circadian clock protein reverse erythroblastosis virus (REV)-ERBα is implicated in the pathogenesis of various diseases, including cancer and myocardial infarction. Emerging evidence suggests that SR9009, an agonist of REV-ERBα, regulates multiple signaling molecules independent or dependent of REV-ERBα. However, the impact of SR9009 on renal fibrosis remains largely unevaluated. In this study, we investigated the effects of SR9009 on transforming growth factor (TGF)-β1-induced fibrotic responses and elucidated the mechanisms involved. Masson's trichome staining revealed that in the unilateral ureteral obstruction groups, there was a decrease in REV-ERBα expression, accompanied by increased levels of the profibrotic factor TGF-β1 and the fibrosis marker α-smooth muscle actin (α-SMA). REV-ERBα knockdown significantly increased α-SMA expression in NRK-49F cells. SR9009 significantly attenuated unilateral ureteral obstruction-induced fibrosis and TGF-β1-induced fibrotic responses in normal rat kidney fibroblasts (NRK-49F cells). Conversely, the REV-ERBα antagonist SR8278 did not affect TGF-β1-induced fibrotic responses. Mechanistic studies revealed that SR9009 significantly inhibited the phosphorylation of ERK and p38, concomitant with reduced α-SMA levels, suppressing TGF-β1-induced NADPH oxidase 4 (NOX4) mRNA expression in NRK-49F cells. Notably, SR9009 did not influence the expression of dual specificity phosphatase 4, which dephosphorylates MAPKs, including p38. Furthermore, REV-ERBα knockdown did not affect the ability of SR9009 to inhibit TGF-β1-induced fibrotic responses and NOX4 expression in NRK-49F cells. In conclusion, SR9009 exerts a protective role against renal fibrosis independent of REV-ERBα. Therefore, SR9009 is a promising therapeutic agent for the prevention and treatment of renal fibrosis associated with renal failure.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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