Role of SAA1 in mediating renal fibrosis through TLR4-dependent NF-κB activation.

Abstract

Background: Renal fibrosis is a key and irreversible pathological event in the progression of chronic kidney disease (CKD), and inflammatory response plays an important role in this process. Serum amyloid A1 (SAA1), an acute-phase reactant protein, which plays an important role in inflammation as a cytokine; but its specific role in renal fibrosis remains to be studied.

Methods: In this study, SAA1 and TLR4 knockout mice were used to establish unilateral ureteral obstruction (UUO) animal renal fibrosis model, and HK-2 cells were used to establish TGF-β-induced cell fibrosis model. The specific role of SAA1 in renal fibrosis was explored by immunoblotting and immunohistochemistry. Subsequently, this study used molecular docking and Co-Immunoprecipitation to verify the specific mechanism of SAA1 promoting renal fibrosis progression.

Results: We found that SAA1 levels were significantly increased in both in vivo and in vitro fibrosis models. Functional studies have shown that gene knockout or knockdown of SAA1 can significantly reduce the progression of renal fibrosis and limited fibrin deposition. On the contrary, overexpression of SAA1 in HK-2 cells aggravated the process of fibrosis. At the mechanism level, we found that in HK-2 cells, SAA1 can directly bind to TLR4, activate downstream NF-κB signaling pathway, promote the production of various cytokines, and then promote the progress of renal fibrosis. Importantly, knockdown of TLR4 alleviated this process.

Conclusions: This study demonstrates that SAA1 promotes the progression of renal fibrosis through TLR4/NF-κB signaling pathway.