Abstract
Fibrosis is a worldwide public health problem, which typically results from chronic diseases and often leads to organ malfunction. Chronic inflammation has been suggested to be the major trigger for fibrogenesis, yet mechanisms by which inflammatory signals drive fibrogenesis have not been fully elucidated. Total C-21 steroidal glycosides (TCSG) from Baishouwu are the main active components of the root of Cynanchum auriculatum Royle ex Wight, which exert hepatoprotective and anti-inflammation properties. In this study, we established a mouse model with the coexistence of hepatic and renal fibrosis and aimed to investigate the effects of TCSG from Baishouwu on fibrosis and explored the potential mechanisms. The results of biochemical and pathological examinations showed that TCSG from Baishouwu improved liver and kidney function and alleviated hepatic and renal fibrosis by reducing collagen and extracellular matrix deposition in bile duct ligation and unilateral ureteral occlusion (BDL&UUO) mice. According to network pharmacology analysis, the mechanisms underlying the effects of TCSG from Baishouwu on hepatic and renal fibrosis were associated with inflammatory response pathways, including “Signaling by interleukins”, “MAP kinase activation”, “MyD88 cascade initiated on plasma membrane”, and “Interleukin-1 family signaling”. Regression analysis and western blot results revealed that IL-1β/MyD88 inflammation signaling played an essential role in the anti-fibrotic effects of TCSG from Baishouwu. Further data displayed that TCSG from Baishouwu affected inflammatory response and extracellular matrix deposition via suppressing the activation of p38 MAPK/JNK and NF-κB p65 signaling cascades both in the liver and kidney of BDL&UUO mice. Thus, our findings suggest TCSG from Baishouwu as a natural regimen against hepatic and renal fibrosis and provide direct evidence that IL-1β/MyD88 signaling crucially contributes to hepatic and renal fibrosis and modulates liver-kidney crosstalk by maintaining tight control over inflammatory responses.
Highlights
Fibrosis is a pathological response characterized by abnormal hyperplasia and excessive deposition of extracellular matrix (ECM) during the process of repair after tissue damage, which has been considered to account for up to 45% of all deaths in the industrialized world (Distler and Györfi, 2019; Henderson et al, 2020)
We found that Total C-21 steroidal glycosides (TCSG) from Baishouwu alleviated the dysfunction of the liver and kidney and reduced the degree of fibrosis both in the liver and kidney by inhibiting the generation of collagen in bile duct ligation and unilateral ureteral occlusion (BDL&UUO) mice
Network pharmacology analysis showed that inflammation response was a major contributing factor to the anti-fibrotic effects of TCSG from Baishouwu on the liver and kidney
Summary
Fibrosis is a pathological response characterized by abnormal hyperplasia and excessive deposition of extracellular matrix (ECM) during the process of repair after tissue damage, which has been considered to account for up to 45% of all deaths in the industrialized world (Distler and Györfi, 2019; Henderson et al, 2020). During the pathological process of a variety of chronic diseases, excessively accumulated ECM results in fibrogenesis and increases tissue hardness, which subsequently blocks the diffusion of oxygen and nutrients, further damaging the organs, hepatic and renal fibrosis are commonly detected in clinical practice (Weiskirchen et al, 2019; Zhao et al, 2020). Increasing pieces of evidence establish that chronic kidney disease can lead to liver dysfunction, contribute to the development of non-alcoholic fatty liver disease, and associate metabolic disturbances (Musso et al, 2015; Marcuccilli and Chonchol, 2016). These findings drove a popular area of scientific interest in liver-kidney organ crosstalk during the last decade. The related pathogenetic mechanisms are not fully known that it is necessary to elucidate the complex and intertwined mechanisms linking hepatic and renal fibrosis and develop effective antifibrotic therapeutic strategies
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