Kidney Res Clin Pract.  2023 May;42(3):325-339. 10.23876/j.krcp.22.034.

The flavonoid fisetin ameliorates renal fibrosis by inhibiting SMAD3 phosphorylation, oxidative damage, and inflammation in ureteral obstructed kidney in mice

• Ju HY
• Kim J
• Han SJ

• KMID: 2543787
• DOI: http://doi.org/10.23876/j.krcp.22.034

Abstract

Background
Renal fibrosis is characterized by the accumulation of extracellular matrix and inflammatory cells and kidney dysfunction, which is a major pathway in the progression of chronic kidney disease (CKD). Accumulating evidence indicates that oxidative stress plays a critical role in the initiation and progression of CKD via proinflammatory and profibrotic signaling pathways. Fisetin (3,3′,4′,7-tetrahydroxyflavone) has biological activities including antioxidant, anti-inflammatory, and anti-aging effects. Therefore, we evaluated the antifibrotic effects of fisetin on unilateral ureteral obstruction (UUO)-induced kidneys. Methods: C57BL/6 female mice were subjected to right UUO and intraperitoneally injected every other day with fisetin (25 mg/kg/ day) or vehicle from 1 hour before surgery to 7 days after surgery. Kidney samples were analyzed for renal fibrosis (α-smooth muscle actin [α-SMA] expression, collagen deposition, and transforming growth factor [TGF] β1/SMAD3 signaling pathway), oxidative damage (4-HNE and 8-OHdG expression), inflammation (proinflammatory cytokine/chemokine, macrophage, and neutrophil infiltration), and apoptosis (TUNEL staining). Cultured human proximal tubule cells were treated with fisetin before TGF-β to confirm the TGF-β downstream pathway (SMAD2/3 phosphorylation). Results: We found that fisetin treatment protected against renal fibrosis by inhibiting the phosphorylation of SMAD3, oxidative damage, inflammation, apoptotic cell death, and accumulation of profibrotic M2 macrophages in the obstructed kidneys. In cultured human proximal tubular cells, fisetin treatment inhibited TGF-β1–induced phosphorylation of SMAD3 and SMAD2. Conclusion: Fisetin alleviates kidney fibrosis to protect against UUO-induced renal fibrosis, and could be a novel therapeutic drug for obstructive nephropathy.

Keyword

Antioxidants; Chronic kidney diseases; Fisetin; Inflammation; Kidney fibrosis; Ureteral obstruction