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

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.

Shenkang Injection for Treating Renal Fibrosis-Metabonomics and Regulation of E3 Ubiquitin Ligase Smurfs on TGF-β/Smads Signal Transduction

“…Previous research has shown that Shenkang injection can negatively regulate TGF-/Smads signaling by lowering TGF- and P-smad3 expression in 5/6 nephrectomized rats, thereby delaying the progression of renal fibrosis and EMT of renal tubular epithelial cells ( Wu et al, 2015 ). Luo et al (2021) showed that SKI and its components (including chrysophenol, emoflavin, and emoflavic acid) can target the IƙB/NF-ƙB and Keap1/Nrf2 ( Chen et al, 2019 ) signaling pathways to inhibit oxidative stress and inflammation, thereby preventing renal fibrosis. The Janus kinase/signal transduction and transcriptional activator (JAK/STAT) pathway is a multipotent signal cascade of multiple growth factors and cytokines, and activation of the JAK/STAT pathway is increased in renal interstitial fibroblasts induced by unilateral ureteral obstruction (UUO) ( Darnell et al, 1994 ).…”

TGF-β/Smad Signaling Pathway in Tubulointerstitial Fibrosis

“…Therefore, the studies of TCMs have attracted attention owing to its superiority in the treatment of refractory diseases ( Chen et al, 2016b ; Li et al, 2021a ; Shao G. et al, 2021 ; Wang Y. W. et al, 2021 ; Yang and Wu, 2021 ). A variety of compounds isolated from natural products have been protected against renal fibrosis ( Feng et al, 2019b ; Luo et al, 2021 ; Shao M. et al, 2021 ; Zhao et al, 2011 ; Zhou F. et al, 2021 ). Therefore, natural products have attracted more and more attention around the world and are committed to the development of new drugs.…”

Recent Advances in Clinical Diagnosis and Pharmacotherapy Options of Membranous Nephropathy

“…Intriguingly, natural products are one of the most promising therapies for a broad spectrum of refractory diseases including coronavirus disease 2019 and its complications ( Chen et al, 2018a ; Chen et al, 2018b ; Izzo et al, 2020 ; Yang et al, 2021a ; Yang et al, 2021b ; Zhang et al, 2021b ; Singla et al, 2021 ; Zuo et al, 2021 ). Mounting natural products have been demonstrated to exhibit excellent efficacy for CKD treatment ( Wang et al, 2018b ; Zhang et al, 2020c ; Geng et al, 2020 ; Meng et al, 2020 ; Miao et al, 2020 ; Lan, 2021 ; Li et al, 2021 ; Luo et al, 2021 ; Miao et al, 2022 ; Yu et al, 2022 ). Although a number of natural products could mitigate MN, the natural products in MN application are still in its infancy compared with CKD.…”