GRAMINE MITIGATES RENAL FIBROSIS BY TARGETING NF-κB/NLRP3 AND TGF-β1/SMAD SIGNALING

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GRAMINE MITIGATES RENAL FIBROSIS BY TARGETING NF-κB/NLRP3 AND TGF-β1/SMAD SIGNALING

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Co-author 1

Shobhit Gairola shobhitgairola1@gmail.com National Institute of Pharmaceutical Education and Research, Raebareli Pharmacology and Toxicology Lucknow India *

Co-author 2

Archana Bhatta archanabhatta933@gmail.com National Institute of Pharmaceutical Education and Research, Raebareli Pharmacology and Toxicology Lucknow India -

Co-author 3

Tushar Mishra mishratushar951@gmail.com National Institute of Pharmaceutical Education and Research, Raebareli Pharmacology and Toxicology Lucknow India -

Co-author 4

Ravinder K. Kaundal ravinderkaundal@gmail.com National Institute of Pharmaceutical Education and Research, Raebareli Pharmacology and Toxicology Lucknow India -

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Introduction

Persistent inflammation and interstitial fibrosis are central determinants of chronic kidney disease (CKD) progression. Gramine (GMN), an indole alkaloid with diverse pharmacological activities, remains unexplored for its renoprotective and antifibrotic potential. This study systematically investigates the therapeutic efficacy of GMN in mitigating renal fibrosis by modulating fibro-inflammatory pathways.

Methods

Potential GMN targets associated with renal fibrosis were identified using network pharmacology analysis. Central hub genes were determined through CytoNCA-based topological analysis, followed by Gene Ontology and pathway enrichment to predict key regulatory mechanisms. Experimental validation was performed in transforming growth factor-β1 (TGF-β1)-stimulated normal rat kidney fibroblasts (NRK-49F) cells and a unilateral ureteral obstruction (UUO)-induced CKD model in mice.

Results

Network pharmacology analysis identified 110 GMN-associated target genes implicated in renal fibrosis, including key regulators of the TGF-β1 signaling pathway. GMN treatment reduced the expression of TGF-β receptor II (TGFBRII) and p-Smad2/3, thereby inhibiting the fibroblast-to-myofibroblast transition and subsequently decreasing collagen I and fibronectin expression in NRK-49F cells. In vivo, oral administration of GMN markedly attenuated UUO-induced renal injury, oxidative stress, and histological changes. GMN suppressed NF-κB-mediated priming of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and inhibited IL-1β maturation, thereby alleviating renal inflammation. Furthermore, GMN significantly mitigated the fibrotic cascade in obstructed kidneys, characterized by overexpression of TGF-β1, TGFBRII, p-Smad2/3, alpha-smooth muscle actin (α-SMA), and extracellular matrix (ECM) components, demonstrating its potential to prevent pathological matrix remodeling and fibrosis progression.

Conclusion

GMN attenuates UUO-induced renal fibrosis by inhibiting the NF-κB/NLRP3 inflammasome axis and TGF-β1/Smad signaling pathway.

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