Sanqi Oral Solution Mitigates Proteinuria in Rat Passive Heymann Nephritis and Blocks Podocyte Apoptosis via Nrf2/HO-1 Pathway.

Peng Xu,Jinchu Liu,Kun Bao,Wei Mao,Bidan Zheng,Zhisheng Lu,Ruimin Tian,Lihua Huang,Chuang Li,Bo Liu,Jing Zhang,Xiaowan Wang

doi:10.3389/fphar.2021.727874

Abstract

Idiopathic membranous nephropathy (IMN) is the most common pathological type in adult nephrotic syndrome where podocyte apoptosis was found to mediate the development of proteinuria. Sanqi oral solution (SQ), an effective Chinese herbal preparation clinically used in treatment of IMN for decades, plays an important role in reducing proteinuria, but the underlying mechanisms have not been fully elucidated yet. The current study tested the hypothesis that SQ directly lessens proteinuria in IMN by reducing podocyte apoptosis. To investigate the effects of SQ, we established the experimental passive Heymann nephritis (PHN) rat model induced by anti-Fx1A antiserum in vivo and doxorubicin hydrochloride (ADR)-injured apoptotic podocyte model in vitro. SQ intervention dramatically reduced the level of proteinuria, together with the rat anti-rabbit IgG antibodies, complement C3, and C5b-9 deposition in glomerulus of PHN rats, accompanied by an elevation of serum albumin. Protein expression of synaptopodin, marker of podocyte injury, restored after SQ administration, whereas the electron microscopic analysis indicated that fusion of foot processes, and the pachynsis of glomerular basement membrane was markedly diminished. Further studies showed that SQ treatment could significantly inhibit podocyte apoptosis in PHN rats and ADR-injured podocytes, and protein levels of Cleaved Caspase-3 or the ratio of Bax/Bcl-2 were significantly decreased with SQ treatment in vivo or in vitro. Moreover, we found that the nuclear factor erythroid 2–related factor-2/heme oxygenase 1 (Nrf2/HO-1) pathway mediated the anti-apoptosis effective of SQ in podocyte. Thus, SQ mitigates podocyte apoptosis and proteinuria in PHN rats via the Nrf2/HO-1 pathway.

Highlights

Idiopathic membranous nephropathy (IMN) is a unique glomerulonephritis, and remains the leading identifiable pathological type of nephrotic syndrome in adults (van de Logt et al, 2019)
Present data revealed that passive Heymann nephritis (PHN) rats developed severe proteinuria, and 24-h proteinuria was significantly elevated from Day 5
Podocyte apoptosis (B) in PHN rats effectively deteriorated with the treatment of SQ and CP (n 6)

Summary

Introduction

Idiopathic membranous nephropathy (IMN) is a unique glomerulonephritis, and remains the leading identifiable pathological type of nephrotic syndrome in adults (van de Logt et al, 2019). Considering the distinction of prognosis, it is proposed that different therapeutic regimens should be established according to the three risk groups of IMN (“low risk” group, “medium risk” group, and “high risk” group) classified by the Toronto Risk Score, and the treatment regimens are observation, immunosuppressive treatment (IST) after observation, and immediate IST (Angioi et al, 2018). A long observative phase (at least 6 months) that needs to assess the risk score will extend delay for the start of IST (van den Brand et al, 2012). Inappropriate medical decision for evaluation of risk groups may result in delay of treatment or increase unnecessary side effects of IST (Xie et al, 2015). The predicament provides a therapeutic window for the treatment of IMN with traditional Chinese medicine

Methods

Results

Conclusion