Podocarpusflavone alleviated renal fibrosis in obstructive nephropathy by inhibiting Fyn/Stat3 signaling pathway

Area of Science:

• Nephrology
• Pharmacology
• Cell Biology

Background:

• Tubulointerstitial fibrosis is a hallmark of end-stage renal disease.
• Limited therapeutic options and unknown mechanisms necessitate new treatments.
• Unilateral ureteral obstruction (UUO) is a model for studying renal fibrosis and inflammation.

Purpose of the Study:

• To investigate the renoprotective effects of podocarpusflavone (POD) in a rodent model of kidney disease.
• To elucidate the underlying molecular mechanisms of POD's action.
• To evaluate POD's therapeutic potential for renal fibrosis and inflammation.

Main Methods:

• In vivo studies using a unilateral ureteral obstruction (UUO) rodent model.
• In vitro experiments with TGF-β1-stimulated renal tubular epithelial cells and LPS-induced RAW264.7 cells.
• Histological and immunohistochemical analyses, including assessment of macrophage infiltration, α-SMA, Col1a1, and fibronectin deposition.
• Western blot analysis to examine Fyn activation and Stat3 phosphorylation.
• Gain-of-function assays using lentivirus-mediated Fyn overexpression.

Main Results:

• POD treatment attenuated renal fibrosis and inflammation in the UUO model.
• POD reduced macrophage infiltration and deposition of α-SMA, Col1a1, and fibronectin.
• POD ameliorated fibrosis in renal tubular cells and inflammation in macrophages in vitro.
• POD inhibited Fyn activation and Stat3 phosphorylation, suggesting a role for the Fyn/Stat3 pathway.
• Forced expression of Fyn abolished POD's protective effects, confirming the pathway's involvement.

Conclusions:

• Podocarpusflavone (POD) demonstrates significant renoprotective effects against tubulointerstitial fibrosis and inflammation.
• POD exerts its therapeutic action by modulating the Fyn/Stat3 signaling pathway.
• POD holds potential as a novel therapeutic agent for renal diseases characterized by fibrosis and inflammation.