Paeoniflorin Inhibits Mesangial Cell Proliferation and Inflammatory Response in Rats With Mesangial Proliferative Glomerulonephritis Through PI3K/AKT/GSK-3β Pathway

Bihao Liu,Yuan Zhou,Ruirui Lu,Jianping Song,Lixia Bai,Peichun Zhang,Jiuyao Zhou,Jin Lin,Dandan Chen,Honglian Li,Yifan Wu,Xusheng Liu,Junbiao Wu,Chunling Liang

doi:10.3389/fphar.2019.00978

Abstract

Mesangial proliferative glomerulonephritis (MPGN) is the most common type of chronic kidney disease in China, characterized by mesangial cell proliferation and inflammatory response. Paeoniflorin, an effective composition extracted from Radix Paeoniae Alba, has been used for various kinds of kidney diseases. However, there are no studies reporting the effects of paeoniflorin on MPGN. The present study aims to investigate whether paeoniflorin plays a role in MPGN and confirm the underlying molecular mechanisms. Our results manifested that paeoniflorin strongly restrained 24 h urinary protein and promoted renal function and dyslipidemia in a MPGN rat model. Moreover, paeoniflorin attenuated mesangial cell proliferation and inflammation both in MPGN rats and human mesangial cells (HMCs) treated with lipopolysaccharide (LPS). In detail, paeoniflorin decreased the number of mesangial cells and expressions of proliferation marker Ki67 in MPGN rats. Paeoniflorin also inhibited HMC proliferation and blocked cell cycle progression. In addition, the contents of inflammatory factors and the expressions of macrophage marker iNOS were decreased after paeoniflorin treatment. Furthermore, we found that the protective effect of paeoniflorin was accompanied by a strong inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT/glycogen synthase kinase (GSK)-3β pathway. Paeoniflorin enhanced the inhibitory effect of PI3K inhibitor LY294002 and suppressed the activated effect of PI3K agonist insulin-like growth factor 1 (IGF-1) on PI3K/AKT/GSK-3β pathway. In conclusion, these results demonstrated that paeoniflorin ameliorates MPGN by inhibiting mesangial cell proliferation and inflammatory response through the PI3K/AKT/GSK-3β pathway.

Highlights

Mesangial proliferative glomerulonephritis (MPGN) is defined by pathological injury pattern with increased cell number and extracellular matrix in the mesangial area (Qin et al, 2013; Yang et al, 2018)
The present study aims to investigate the effects of paeoniflorin on MPGN in vivo and in vitro and explore the molecular mechanism related to the PI3K/AKT/glycogen synthase kinase (GSK)-3β pathway
Our results showed that paeoniflorin decreased 24 h urinary protein since the seventh week till the end of the animal experiment (Figure 1A)

Summary

Introduction

Mesangial proliferative glomerulonephritis (MPGN) is defined by pathological injury pattern with increased cell number and extracellular matrix in the mesangial area (Qin et al, 2013; Yang et al, 2018). Proliferation and inflammation of mesangial cells plays a crucial role in the progression of MPGN. The serine/threonine kinase (AKT), a downstream kinase of PI3K, plays an important role in cell death and survival (Li et al, 2018). One of the major effectors downstream of AKT is glycogen synthase kinase (GSK)-3β, by initiating phosphorylation at its serine 9 residue (Wang et al, 2014). Research proved that the activation of the PI3K/AKT/ GSK-3β signaling pathway is vital for cell proliferation (Wang et al, 2012). Our previous study verified that the AKT/GSK-3β pathway is activated when mesangial cells proliferate, and it could be an efficient path to suppress abnormal proliferation and inflammation response through down-regulating the AKT/ GSK-3β pathway (Wu et al, 2018)

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Conclusion