Pinocembrin alleviates renal ischemia–reperfusion injury/unilateral ureteral obstruction (UUO)‐generated renal fibrosis by targeting the CYP1B1/ROS/MAPK axis

Jan 29, 2025The FEBS journal

Pinocembrin may reduce kidney damage and scarring from blood flow loss and blockage by affecting oxidative stress and cell signaling pathways

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Abstract

Oral pinocembrin (PIN) administration significantly reduced tissue damage and renal dysfunction in acute kidney injury models.

PIN was shown to mitigate renal dysfunction caused by ischemia-reperfusion injury and reduce renal fibrosis from unilateral ureteral obstruction.
The expression of fibrotic markers decreased in response to PIN treatment, as evidenced by various staining techniques.
In HK-2 cells, PIN also demonstrated protective effects under conditions of hypoxia-reoxygenation and TGF-β1 treatment.
Bioinformatics analysis indicated that PIN may target cytochrome P450 1B1 (CYP1B1) and influence the mitogen-activated protein kinase (MAPK) pathway.
Experiments revealed that PIN reduced CYP1B1 expression, reactive oxygen species production, and inflammation associated with the MAPK pathway.
Overexpression of CYP1B1 negated the protective effects of PIN on reactive oxygen species generation and MAPK pathway activation.

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In our research, we constructed models of renal ischemia-reperfusion (I/R)-exposed acute kidney injury (AKI) and unilateral ureteral obstruction (UUO)-stimulated renal fibrosis (RF) in C57BL/6 mice and HK-2 cells. We firstly authenticated that oral pinocembrin (PIN) administration obviously mitigated tissue damage and renal dysfunction induced by I/R injury, and PIN attenuated UUO-caused RF, as confirmed by the reduced expression of fibrotic markers as well as hematoxylin-eosin (H&E), Sirius red, immunohistochemistry, and Masson staining. Meanwhile, the beneficial role of PIN was again demonstrated in HK-2 cells with hypoxia-reoxygenation (H/R) or transforming growth factor beta-1 (TGF-β1) treatment. Importantly, the "ingredient-target-pathway-disease" network was established through bioinformatics analysis and molecular docking, which showed that PIN may target cytochrome P450 1B1 (CYP1B1) and modulate the mitogen-activated protein kinase (MAPK) pathway to exert its impact during injury. Furthermore, experiments confirmed that PIN usage remarkably constrained CYP1B1 expression, reactive oxygen species (ROS) production, MAPK-pathway-associated inflammation, or apoptosis during I/R injury or UUO exposure. PIN also ameliorated the elevated protein phosphorylation of MAPK pathway components [p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 1 (JNK ERK and JNK)], which validated the PIN-induced inhibition of the MAPK signaling pathway in renal I/R or UUO injury. Moreover, the AAV9 (adeno-associated virus 9)-packed CYP1B1 or pcDNA-CYP1B1 overexpression plasmid was utilized to treat C57BL/6 mice or HK-2 cells to overexpress CYP1B1, respectively. Notably, CYP1B1 overexpression considerably abolished PIN's restriction impact on ROS generation and MAPK pathway activation. In conclusion, via bioinformatics analysis, molecular docking, animal model, and cellular experiments, we proved that PIN alleviates renal I/R injury/UUO-generated renal fibrosis through regulating the CYP1B1/ROS/MAPK axis.

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