Citral Is Renoprotective for Focal Segmental Glomerulosclerosis by Inhibiting Oxidative Stress and Apoptosis and Activating Nrf2 Pathway in Mice

Shun-Min Yang,Kuo-Feng Hua,Yu-Chuan Lin,Ann Chen,Shuk-Man Ka,Chen-Lung Ho,Louis Kuoping Chao,Jia-Ming Chang,Vassiliki A Boussiotis

doi:10.1371/journal.pone.0074871

Abstract

The pathogenesis of focal segmental glomerulosclerosis (FSGS) is considered to be associated with oxidative stress, mononuclear leukocyte recruitment and infiltration, and matrix production and/or matrix degradation, although the exact etiology and pathogenic pathways remain to be determined. Establishment of a pathogenesis-based therapeutic strategy for the disease is clinically warranted. Citral (3,7-dimethyl-2,6-octadienal), a major active compound in Litsea cubeba , a traditional Chinese herbal medicine, can inhibit oxidant activity, macrophage and NF-κB activation. In the present study, first, we used a mouse model of FSGS with the features of glomerular epithelial hyperplasia lesions (EPHLs), a key histopathology index of progression of FSGS, peri-glomerular inflammation, and progressive glomerular hyalinosis/sclerosis. When treated with citral for 28 consecutive days at a daily dose of 200 mg/kg of body weight by gavage, the FSGS mice showed greatly reduced EPHLs, glomerular hyalinosis/sclerosis and peri-glomerular mononuclear leukocyte infiltration, suggesting that citral may be renoprotective for FSGS and act by inhibiting oxidative stress and apoptosis and early activating the Nrf2 pathway. Meanwhile, a macrophage model involved in anti-oxidative and anti-inflammatory activities was employed and confirmed the beneficial effects of citral on the FSGS model.

Highlights

Focal segmental glomerulosclerosis (FSGS) manifests with heavy proteinuria in association with focal, but progressive, glomerular sclerosis in the kidney [1,2,3]
Light microscopy showed that characteristic glomerular epithelial hyperplasia lesions (EPHLs), suggestive of progression of FSGS lesions, glomerular hyalinosis/sclerosis and peri-glomerular inflammation were both seen at days 14 and 28 in FSGS+vehicle mice, but these renal lesions were greatly decreased in FSGS+Citral mice (Figure 1D)
Our study demonstrated that Citral, a purified major active component of Litsea cubeba, had renoprotective effects in a FSGS mouse model, including preventing the kidney from glomerular EPHLs, a key histopathology index of progression of FSGS, and from glomerular hyalinosis/sclerosis and mononuclear leukocyte infiltration

Summary

Introduction

Focal segmental glomerulosclerosis (FSGS) manifests with heavy proteinuria in association with focal, but progressive, glomerular sclerosis in the kidney [1,2,3]. Corticosteroids and other immunomodulatory agents are commonly used to treat these patients [6,7], they result in an unsatisfactory outcome in terms of progression of renal inflammation and fibrosis [8,9] and have various side-effects [10,11]. The etiology and pathogenesis of FSGS are poorly understood, its pathogenic pathways may involve oxidative stress [13,14,15], inflammation associated with mononuclear leukocyte recruitment [16,17,18], and promotion of matrix production and/or degradation [19]. Nrf has been shown to regulate cellular production of antioxidants and protects against oxidative stress in chronic renal failure [28,29], renal inflammation [30] and fibrosis [31,32]

Methods

Results

Conclusion