Tongxinluo Protects against Hypertensive Kidney Injury in Spontaneously-Hypertensive Rats by Inhibiting Oxidative Stress and Activating Forkhead Box O1 Signaling.

Wei-min Luo,Yu-xia Zhao,Jing Kong,Yan Gong,Rui-xue Yang,Xiao-qiong Liu,Nick Ashton

doi:10.1371/journal.pone.0145130

Abstract

Hypertension is an independent risk factor for the progression of chronic renal failure, and oxidative stress plays a critical role in hypertensive renal damage. Forkbox O1(FoxO1) signaling protects cells against oxidative stress and may be a useful target for treating oxidative stress-induced hypertension. Tongxinluo is a traditional Chinese medicine with cardioprotective and renoprotective functions. Therefore, this study aimed to determine the effects of Tongxinluo in hypertensive renal damage in spontaneously hypertensive rats(SHRs)and elucidate the possible involvement of oxidative stress and FoxO1 signaling in its molecular mechanisms. SHRs treated with Tongxinluo for 12 weeks showed a reduction in systolic blood pressure. In addition to increasing creatinine clearance, Tongxinluo decreased urinary albumin excretion, oxidative stress injury markers including malondialdehyde and protein carbonyls, and expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and its activity in SHR kidneys. While decreasing phosphorylation of FoxO1, Tongxinluo also inhibited the phosphorylation of extracellular signal-regulated kinase1/2 and p38 and enhanced manganese superoxide dismutase and catalase activities in SHR kidneys. Furthermore, histology revealed attenuation of glomerulosclerosis and renal podocyte injury, while Tongxinluo decreased the expression of α-smooth muscle actin, extracellular matrixprotein, transforming growth factor β1 and small mothers against decapentaplegic homolog 3,and improved tubulointerstitial fibrosis in SHR kidneys. Finally, Tongxinluo inhibited inflammatory cell infiltration as well as expression of tumor necrosis factor-α and interleukin-6. In conclusion, Tongxinluo protected SHRs against hypertension-induced renal injury by exerting antioxidant, antifibrotic, and anti-inflammatory activities. Moreover, the underlying mechanisms of these effects may involve inhibition of oxidative stress and functional activation of FoxO1 signaling.

Highlights

In clinic practice, the hypertension-induced renal injury is an important factor in the pathogenesis of end-stage nephropathy and the need for dialysis[1]
There was no significant difference in body weight, kidney weight, and urinary volume among the three groups (Table 2)
This study demonstrated for the first time that TXL treatment protected spontaneously hypertensive rats (SHRs) against hypertensive renal injury by reducing the systolic blood pressure (SBP), decreasing urinary albumin excretion, increasing creatinine clearance, and improving glomerulosclerosis and tubulointerstitial fibrosis

Summary

Introduction

The hypertension-induced renal injury is an important factor in the pathogenesis of end-stage nephropathy and the need for dialysis[1]. Renal injury related to hypertension is characterized by glomerular and tubulointerstitial damages, which eventually lead to renal dysfunction[2]. Oxidative stress plays a critical role in the pathological development of renal injury related to hypertension[5]. Reactive oxygen species (ROS) generated during oxidative stress influence most types of intrinsic kidney cells. Oxidative stress determines podocyte apoptosis and generation of segmental glomerulosclerosis, thereby influencing glomerular permeability[6]. Oxidative stress and inflammatory responses act synergistically in the pathogenesis of renal injury[8]. Antioxidant therapy is an important aspect of the therapeutic strategy for hypertensive kidney damage[3, 9]

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Conclusion