Nootkatone confers antifibrotic effect by regulating the TGF-β/Smad signaling pathway in mouse model of unilateral ureteral obstruction

Chronic kidney disease (CKD) with underlying interstitial fibrosis is often associated with end-stage renal disease (ESRD). In the present study, we investigated the renoprotective and antifibrotic potential of nootkatone (NTK), a bioactive sesquiterpene, in an experimental model of renal fibrosis. Unilateral ureteral obstruction (UUO) model was performed to induce renal fibrosis in Balb/C mice. The animals were randomly assigned into 5 groups: sham, NTK control, UUO control, UUO and NTK 5 mg/kg, and UUO and NTK 10 mg/kg. Animals received NTK at a dose of 5 mg/kg and 10 mg/kg orally for the next 14 consecutive days. UUO induced histological alterations, accumulation of extracellular matrix (ECM) components including collagens, fibronectin, and alpha-smooth muscle actin (α-SMA), activation of the transforming growth factor-β (TGF-β)/Smad signaling and oxidative damage in the obstructed kidneys. Our study revealed that NTK (10 mg/kg) inhibits UUO mediated kidney fibrosis in vivo. Administration of NTK (10 mg/kg) prevented the activation of the TGF-β/Smad signaling, expression of ECM components, markedly attenuated the renal tubular injury and fibrosis area (% area: 6.66 ± 1.45% vs UUO: 26.33 ± 2.90%). Administration of NTK at 10 mg/kg significantly restored the endogenous antioxidants and prevented the reactive oxygen species generation (25.31 ± 1.65% vs UUO: 45.01 ± 4.85%) and reduced the level of tumor necrosis factor (TNF)-α (95.22 ± 12.39 vs UUO: 215.57 ± 60.45 pg/mg protein) in the kidneys. Altogether, our findings suggest that NTK might be a budding therapeutic candidate for renal fibrosis.