Enhanced eNOS/nitric oxide production by nebivolol interferes with TGF-ß1/Smad3 signaling and collagen I deposition in the kidney after prolonged tacrolimus administration.
Life Sci
; : 122995, 2024 Aug 17.
Article
in En
| MEDLINE
| ID: mdl-39159720
ABSTRACT
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-ß/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-ß1/Smad3 signaling. MATERIALS ANDMETHODS:
To illustrate the proposed mechanism of nebivolol, Nω-nitro-L-arginine methyl ester (L-NAME); nitric oxide synthase inhibitor; was co-administrated with nebivolol. Rats were treated for 30â¯days as control, tacrolimus, tacrolimus/nebivolol, tacrolimus/L-NAME, and tacrolimus/nebivolol/L-NAME groups. KEYFINDINGS:
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-ß1/Smad3 signaling induced by tacrolimus, where the addition of L-NAME abolished the 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-ß1 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-ß1/Smad3 fibrotic signaling via the enhancement of endothelial NO production, thus curbing renal fibrosis development.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Life Sci
Year:
2024
Document type:
Article