Insights into the role of P2X7R/DUSP6/ERK1/2 and SIRT2/MDM2 signaling in the nephroprotective effect of berberine against cisplatin-induced renal fibrosis in rats.

Autor: Ahmedy OA; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: omaima.ali@pharma.cu.edu.eg., El-Tanbouly DM; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Egypt., Al-Mokaddem AK; Pathology Department, Faculty of Veterinary Medicine, Cairo University, Egypt., El-Said YAM; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Egypt.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2022 Nov 15; Vol. 309, pp. 121040. Date of Electronic Publication: 2022 Oct 05.
DOI: 10.1016/j.lfs.2022.121040
Abstrakt: Aims: Several signaling events have been identified for mediating cisplatin-induced chronic inflammation and progressive renal fibrosis, but the majority of them have not yet been established as therapeutic targets. This study investigated the modulatory effects of berberine on purinergic 2X7 receptors (P2X7R) and some potential intracellular profibrogenic signaling as molecular mechanisms that could hinder renal fibrosis associated with cisplatin administration in rats.
Main Methods: For induction of kidney injury, rats were injected with cisplatin (1 mg/kg, i.p.) daily for two weeks. Concurrently, the rats were treated with berberine (100 or 200 mg/kg, p.o). The gene expressions of P2X7R, dual-specificity phosphatase 6 (DUSP6), and murine double-minute 2 (MDM2) were determined. The expressions of alpha smooth-muscle actin and tumor necrosis factor alpha (TNF-α) were assessed by immunohistochemical staining. Phosphorylated extracellular signal-regulated kinase 1/2, (p-ERK1/2) was evaluated by western blotting. Sirtuin 2 (SIRT2), kidney injury molecule-1, and galectin-3 were measured by enzyme-linked immunosorbent assay. The degree of renal fibrosis was assessed by microscopic examination and picrosirius red staining.
Key Findings: Berberine effectively inhibited cisplatin-induced renal histopathological changes, enhanced renal function, and markedly mitigated inflammatory and fibrotic alterations as well as TNF-α protein expression. Additionally, P2X7R, p-ERK1/2, MDM2, and SIRT2 were suppressed and DUSP6 was upregulated by berberine.
Significance: The nephroprotective effects of berberine were mediated in part by downregulating P2X7R and modulating DUSP6-mediated inactivation of ERK1/2 as well as by suppressing SIRT2/MDM2-triggered renal fibrosis.
Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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