Therapeutic potential of nicorandil vs nebivolol in attenuating PKC/P38MAPK signaling via PPARγ/KLOTHO/CREB pathway signaling: molecular docking and experimental validation in rat model of unilateral ureteric obstruction.
Khalifa Amira Karam, Galal Amr M, Saber Sameh, El-Sayed Ahmed F, Alsibaee Aishah M, Saeedi Tahani, Alsubhi Samia, Miski Samar F, Aboulhoda Basma Emad, Mohamed Eman Emad Eldin, Wanas Hanaa
Abstract
UNLABELLED: This study is designed to highlight the comparative efficacy of nicorandil (NO donor/KATP opener) vs nebivolol (β1blocker with NO-induced vasodilatory and antioxidant actions) in a rat model of unilateral ureteric obstruction (UUO) to assess whether mitigating oxidative stress, inflammatory drive, and apoptosis could modulate UUO -driven fibrogenic remolding.Moreover, their therapeutic potential was further assessed by docking analysis. METHODOLOGY: Sham control group (1); UUO Group (2); Group (3): The nicorandil-treated group, in which rats received 15 mg/kg/day following ureteric obstruction for 21 days, and Group (4): the nebivolol-treated group, in which rats received 2 mg/kg/day orally following ureteric obstruction for 21 days. RESULTS: bioinformatically, Notable findings include nebivolol's superior binding affinity to Catalase, TGFβ1R and LOX-1 and nicorandil's higher affinity to TP53and Smad-3. These interactions suggest that both compounds may mitigate oxidative stress, inflammation, and fibrosis. Nebivolol potentially offers greater renal protection through enhanced suppression of pro-inflammatory signaling. Mechanistically, nebivolol demonstrates superior efficacy through coordinated modulation of key molecular pathways. Nebivolol disrupts the self-amplifying cycle of oxidative stress and inflammation by upregulating SIRT-1, miRNA200a expression restoring Nrf2 activity, and downregulating Keap1 re-establishing redox homeostasis. It further attenuates NF-κB-driven proinflammatory signaling and suppresses downstream PKC/p38 MAPK activation, reducing fibrotic and apoptotic responses. Concurrently, nebivolol enhances protective signaling via PPARγ, Klotho, and CREB, promoting cellular resilience and structural preservation. These multifaceted actions converge to normalize renal function, mitigate tissue injury, and maintain glomerular-tubular integrity. CONCLUSION: By targeting interconnected redox, inflammatory, and apoptotic pathways, nebivolol could emerge as a mechanistically therapeutic candidate, offering promise for repurposing in obstructive nephropathy and potentially in broader contexts of chronic kidney disease characterized by complex molecular dysregulation.
Key Findings
- Nebivolol shows superior binding affinity to Catalase, TGFβ1R, and LOX-1 compared to nicorandil, indicating enhanced potential to mitigate oxidative stress, inflammation, and fibrosis.
- Nebivolol upregulates SIRT-1 and miRNA200a expression, restores Nrf2 activity, and downregulates Keap1, thereby re-establishing redox homeostasis and disrupting the cycle of oxidative stress and inflammation.
- Nebivolol attenuates NF-κB-driven proinflammatory signaling and suppresses PKC/p38 MAPK activation, reducing fibrotic and apoptotic responses while enhancing protective signaling via PPARγ, Klotho, and CREB to preserve renal function.
Clinical Significance
Nebivolol demonstrates therapeutic potential in protecting renal function by targeting oxidative stress and inflammatory pathways, suggesting its utility in managing renal fibrosis and injury associated with unilateral ureteric obstruction.
Citation
Khalifa Amira Karam, Galal Amr M, Saber Samehet al.. Therapeutic potential of nicorandil vs nebivolol in attenuating PKC/P38MAPK signaling via PPARγ/KLOTHO/CREB pathway signaling: molecular docking and experimental validation in rat model of unilateral ureteric obstruction. European journal of pharmacology. 2026-Jun-15.