Shenkang Injection and Its Three Anthraquinones Ameliorates Renal Fibrosis by Simultaneous Targeting IƙB/NF-ƙB and Keap1/Nrf2 Signaling Pathways.

Liang-Pu Luo,Ying-Yong Zhao,Yamei Zhang,Li-Li Ren,Ping Suo,Hong-Jiao Liu

doi:10.3389/fphar.2021.800522

Abstract

Oxidative stress and inflammation are important and critical mediators in the development and progression of chronic kidney disease (CKD) and its complications. Shenkang injection (SKI) has been widely used to treat patients with CKD. Although the anti-oxidative and anti-inflammatory activity was involved in SKI against CKD, its bioactive components and underlying mechanism remain enigmatic. A rat model of adenine-induced chronic renal failure (CRF) is associated with, and largely driven by, oxidative stress and inflammation. Hence, we identified the anti-oxidative and anti-inflammatory components of SKI and further revealed their underlying mechanism in the adenine-induced CRF rats. Compared with control rats, the levels of creatinine, urea, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum were significantly increased in the adenine-induced CRF rats. However, treatment with SKI and its three anthraquinones including chrysophanol, emodin, and rhein could reverse these aberrant changes. They could significantly inhibit pro-fibrotic protein expressions including collagen I, α-SMA, fibronectin, and vimentin in the kidney tissues of the adenine-induced CRF rats. Of note, SKI and rhein showed the stronger inhibitory effect on these pro-fibrotic protein expressions than chrysophanol and emodin. Furthermore, they could improve dysregulation of IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways. Chrysophanol and emodin showed the stronger inhibitory effect on the NF-κB p65 protein expression than SKI and rhein. Rhein showed the strongest inhibitory effect on p65 downstream target gene products including NAD(P)H oxidase subunits (p47phox, p67phox, and gp91phox) and COX-2, MCP-1, iNOS, and 12-LO in the kidney tissues. However, SKI and rhein showed the stronger inhibitory effect on the significantly downregulated anti-inflammatory and anti-oxidative protein expression nuclear Nrf2 and its target gene products including HO-1, catalase, GCLC, and NQO1 in the Keap1/Nrf2 signaling pathway than chrysophanol and emodin. This study first demonstrated that SKI and its major components protected against renal fibrosis by inhibiting oxidative stress and inflammation via simultaneous targeting IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways, which illuminated the potential molecular mechanism of anti-oxidative and anti-inflammatory effects of SKI.

Highlights

Organ fibrosis is a pathological extension of the normal wound healing process characterized by oxidative stress and inflammation; myofibroblast activation and migration; and excessive synthesis, deposition, and remodeling of extracellular matrix (ECM) components, mainly including collagen, fibronectin, and α-smooth muscle actin (α-SMA) (Miao et al, 2021a)
Treatment with emodin significantly lowered the levels of creatinine, urea, TC, and low-density lipoprotein cholesterol (LDL-C) in the adenine-induced chronic renal failure (CRF) group, while the levels of uric acid and triglyceride were decreased in the adenine-induced CRF group treated by emodin, but did not arrive at statistical significance
Shenkang injection (SKI) and rhein showed the stronger inhibitory effect on the pro-fibrotic protein expression than chrysophanol and emodin. These results demonstrated that SKI and three anthraquinones protected against renal fibrosis in the adenine-induced CRF rats

Summary

Introduction

Organ fibrosis is a pathological extension of the normal wound healing process characterized by oxidative stress and inflammation; myofibroblast activation and migration; and excessive synthesis, deposition, and remodeling of extracellular matrix (ECM) components, mainly including collagen, fibronectin, and α-smooth muscle actin (α-SMA) (Miao et al, 2021a). A variety of pathophysiological principles is shared by many fibrotic-associated diseases, such as cirrhosis, kidney fibrosis, myocardial fibrosis, and idiopathic pulmonary fibrosis (Miao et al, 2021a). Renal fibrosis, characterized by tubulointerstitial fibrosis and glomerulosclerosis, is a chronic and progressive process influencing renal functions during aging and in chronic kidney disease (CKD), regardless of the cause (Bhargava et al, 2021; Li et al, 2021; Medina Rangel et al, 2021). About 11% of patients with stage 3 CKD will inevitably progress to end-stage renal disease (ESRD), requiring renal replacement therapies such as dialysis and transplantation (Chauveau, 2018; Jain et al, 2019; Carta et al, 2020; Sawhney and Gill, 2020). The costs to care for patients with CKD are two times compared with as large as ESRD costs

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