Aegle marmelos attenuates high glucose induced renal cell fibrosis via redox homeostasis maintenance and gasotransmitters modulation

• Aegle marmelos substantially decreases the high glucose induced renal cell fibrosis. • Aegle marmelos mitigates ROS generation by downregulating NOX4 expression. • Aegle marmelos elevates nitrite and hydrogen sulphide level by increasing their synthesing enzymes. • Aegeline, the active component contributes to the beneficial effect of AMLE against high glucose induced renal cell fibrosis. Diabetic kidney disease substantially increases the risk of endstage renal disease necessitating the imperative need for identification of novel drug candidates to prevent disease progression. Aegle marmelos is a well-known plant used in the Indian system of medicine for treating diabetes and its complications, but its molecular mechanism has not been elucidated. Hence, we investigated the mechanistic role of Aegle marmelos leaf extract (AMLE) and its active molecules in protecting high glucose (HG) induced renal cell fibrosis. Normal rat kidney epithelial cells were used to study the effect of AMLE (100 μg/ml) on HG (25 mM) induced renal cell fibrotic events and oxidative imbalance. Gasotransmitters (NO and H 2 S), their respective synthesizing enzymes and their regulatory miRNAs were measured. Molecular docking analysis was performed using Schrodinger software to study the binding interaction of active biomolecules. AMLE alleviated the HG induced renal cell fibrosis by decreasing the expression levels of fibrotic markers and impeded the fibrotic events. AMLE significantly reduced the HG induced ROS generation by decreasing NADPH oxidase 4 (NOX4) expression. AMLE increased the gasotransmitters levels (NO and H 2 S) by augmenting the NOS3 phosphorylation and CBS expression and decreased their regulatory miRNAs (miR-195 and miR-21). Active biomolecule, aegeline significantly combated the HG induced renal cell fibrosis by targeting NOX4 and CBS. We demonstrated the protective effect and mechanistic action of AMLE in preventing HG mediated renal cell fibrosis by regulating the oxidative stress, gasotransmitters, its active biomolecule aegeline plays a beneficial role.