Enhanced eNOS/nitric oxide production by nebivolol interferes with TGF-β1/Smad3 signaling and collagen I deposition in the kidney after prolonged tacrolimus administration.

Autor: Azouz AA; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: amany.azoz@pharm.bsu.edu.eg., Tohamy MA; Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt., Ali FEM; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan., Mahmoud HM; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2024 Oct 15; Vol. 355, pp. 122995. Date of Electronic Publication: 2024 Aug 17.
DOI: 10.1016/j.lfs.2024.122995
Abstrakt: Aims: Tacrolimus is an effective immunosuppressant commonly used post-transplantation and in certain autoimmune diseases. However, its long-term administration is associated with renal fibrosis through transforming growth factor-beta/suppressor of mother against decapentaplegic (TGF-β/Smad) signaling that could be partly attributed to endothelial dysfunction alongside decreased nitric oxide (NO) release. Our study aimed to investigate the prospective renal anti-fibrotic effect of enhanced NO production by nebivolol against tacrolimus-stimulated TGF-β1/Smad3 signaling.
Materials and Methods: To illustrate the proposed mechanism of nebivolol, N ω -nitro-L-arginine methyl ester (L-NAME); nitric oxide synthase inhibitor; was co-administered with nebivolol. Rats were treated for 30 days as control, tacrolimus, tacrolimus/nebivolol, tacrolimus/L-NAME, and tacrolimus/nebivolol/L-NAME groups.
Key Findings: Our results revealed that renal NO content was reduced in tacrolimus-treated rats, while treatment with tacrolimus/nebivolol enhanced NO content via up-regulated endothelial nitric oxide synthase (eNOS), but down-regulated inducible nitric oxide synthase (iNOS) expression. That participated in the inhibition of TGF-β1/Smad3 signaling induced by tacrolimus, where the addition of L-NAME abolished the defensive effects of nebivolol. Subsequently, the deposition of collagen I and alpha-smooth muscle actin (α-SMA) was retarded by nebivolol, emphasized by reduced Masson's trichrome staining. In accordance, there was a strong negative correlation between eNOS and both TGF-β1 and collagen I protein expression. The protective effects of nebivolol were further confirmed by the improvement in kidney function biomarkers and histological features.
Significance: It can be suggested that treatment with nebivolol along with tacrolimus could effectively suppress renal TGF-β1/Smad3 fibrotic signaling via the enhancement of endothelial NO production, thus curbing renal fibrosis development.
Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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