Anti-Renal Fibrosis Effect of Urolithin B, Ellagitannin-Gut Microbial-Derived Metabolites, via TGF-β1/Smad and TLR4/NF-κb Signaling Pathways in a Rat Model of Unilateral Ureteral Obstruction

Abstract

Background: Urolithin B, gut microbiota metabolite of ellagitannins, contributes toward multiple health benefits attributed to ellagitannin-rich foods, has various bioactivities such as anti-inflammatory and anti-aging effects. This study was to investigate the effect of urolithin B on renal fibrosis and the underlying mechanism. Methods: In vivo, unilateral ureteral obstruction (UUO) model was established with or without urolithin B treatment for three weeks. Then, changes in the kidney function and renal pathology were investigated. In vitro, the HK-2 cells were treated with TGF-β1 (10 ng/ml) for 24 h with or without urolithin B administration. Next cell damage and proliferation was evaluated. Findings: In vivo, after urolithin B treatment, UUO-induced kidney injury was significantly ameliorated as shown by the improvement of renal function (BUN and serum creatinine), kidney morphology and the suppression of renal tubular injury markers of TGF-β1, Ang II, α-SMA and Col IV. Meanwhile, the renal inflammatory induced by UUO were also strikingly attenuated in urolithin B-treated rats (TNF-α, IL-6 and MCP-1). In vitro, urolithin B treatment markedly inhibited TGF-β1-induced HK-2 cells fibrosis and proliferation, suppressed TGF-β1 and NF-κB activation. Interpretation: This works suggested that urolithin B contributes critically to the development of chronic kidney pathologies induced by UUO, and modulating TGF-β/Smad and TLR4/NF-κB signaling possibly represent a potential therapeutic strategy to impede renal fibrosis transition. Funding: This work was supported by a grant from the National Natural Science Foundation of China (no. 31770381). Declaration of Interest: The authors declare that there are no conflicts of interest. Ethical Approval: All animal experiment were approved by the ethics committee of Wu Han University, Wu Han, China, and carried in accordance with National institutes of health guide for the care and use of laboratory animals.