Saikosaponin D Inhibits Peritoneal Fibrosis in Rats With Renal Failure by Regulation of TGFβ1/ BMP7 / Gremlin1/ Smad Pathway.

Liu Ruiqi,Pei Ming,Lei Yangyang,Lin Wei,Liu Xinyue,Su Qihang,Chen Junli,Gao Chao,Yang Kang,Yang Hongtao

doi:10.3389/fphar.2021.628671

Abstract

Peritoneal dialysis (PD) can improve the quality of life of patients with kidney disease and prolong survival. However, peritoneal fibrosis can often occur and lead to PD withdrawal. Therefore, it is imperative to better understand how to inhibit and slow down progression of peritoneal fibrosis. This study aimed to investigate the regulatory effect of Saikosaponin d (SSD), a monomer extracted from the plant Bupleurum, on peritoneal fibrosis and the contribution of TGFβ1/BMP7/Gremlin1 pathway cross-talk in this process. To this aim, we used a model 5/6 nephrectomy and peritoneal fibrosis in rats. Rats were divided into four groups, namely a control group (saline administration); a model group (dialysate administration; group M); a SSD group (dialysate and SSD administration); and a positive drug group (dialysate and Benazepril Hydrochloride administration; group M + A). Histological analysis indicated that peritoneal fibrosis occurred in all groups. WB, ELISA, and PCR essays suggested that TGFβ1 and Gremlin1 levels in group M were significantly higher than those in group C, whereas BMP7 expression was significantly lower. TGFβ1, Gremlin1 and BMP7 levels were significantly lower in the group where SSD was administered than in the other groups. The expression of BMP7 in SSD group was significantly increased. In addition, levels of Smad1/5/8 as assessed by PCR, and levels of p-Smad1/5/8 expression as assessed by WB were also significantly higher in the SSD group than in the M group. Expression of vimentin and α-SMA, two important markers of fibrosis, was also significantly decreased. Our study suggests a role for the TGFβ1/BMP7/Gremlin1/Smad pathway in peritoneal fibrosis with potential therapeutic implications. Finally, our results also suggest that the monomer SSD may be able to reverse peritoneal fibrosis via regulation of the TGFβ1/BMP7/Gremlin1/Smad pathway.

Highlights

The incidence of chronic kidney disease has been increasing in recent years (Collaborators, 2013)
In order to understand the putative effect of Saikosaponin d (SSD) on peritoneal fibrosis, we aimed to investigate: 1) whether a cross-talk of theTGFβ1/Bone morphogenic protein 7 (BMP7)/Gremlin1 pathways was involved in the progression of peritoneal fibrosis; 2) whether SSD exerted inhibitory effects on peritoneal fibrosis in rat model of kidney disease; 3) whether a potential regulatory effect of SSD on peritoneal fibrosis was dependent on a TGFβ1/BMP7/ Gremlin1 pathway cross-talk
The RNA expression levels of vimentin and α-SMA, which are closely related to the process of fibrosis, were significantly higher in group M than in group C, but significantly lower in group SSD than in group M. These results suggest that the TGFβ1/BMP7/ Gremlin1 pathway was involved in the process of peritoneal fibrosis both in the presence and absence of the SSD intervention

Summary

Introduction

The incidence of chronic kidney disease has been increasing in recent years (Collaborators, 2013). The number of patients with end-stage renal disease (ESRD) is increasing (McCullough et al, 2019) (Yamagata et al, 2015) (Hsuyuan et al, 2004). Peritoneal dialysis (PD) is a form of renal replacement therapy and an effective way to improve the quality of life and prolong survival of patients with end-stage renal disease. It is estimated that over 250 thousand patients are treated by Saikosaponin D Inhibits Peritoneal Fibrosis. The complications of PD, such as peritonitis and peritoneal fibrosis, can negatively impact the therapeutic effect of PD. Understanding how to inhibit or slow down the progression of peritoneal fibrosis is a clinical priority

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