Atractylenolide III Attenuates Muscle Wasting in Chronic Kidney Disease via the Oxidative Stress-Mediated PI3K/AKT/mTOR Pathway

Abstract

Oxidative stress contributes to muscle wasting in advanced chronic kidney disease (CKD) patients. Atractylenolide III (ATL-III), the major active constituent of Atractylodes rhizome, has been previously reported to function as an antioxidant. This study is aimed at investigating whether ATL-III has protective effects against CKD-induced muscle wasting by alleviating oxidative stress. The results showed that the levels of serum creatinine (SCr), blood urea nitrogen (BUN), and urinary protein significantly decreased in the ATL-III treatment group compared with the 5/6 nephrectomy (5/6 Nx) model group but were higher than those in the sham operation group. Skeletal muscle weight was increased, while inflammation was alleviated in the ATL-III administration group compared with the 5/6 Nx model group. ATL-III-treated rats also showed reduced dilation of the mitochondria, increased CAT, GSH-Px, and SOD activity, and decreased levels of MDA both in skeletal muscles and serum compared with 5/6 Nx model rats, suggesting that ATL-III alleviated mitochondrial damage and increased the activity of antioxidant enzymes, thus reducing the production of ROS. Furthermore, accumulated autophagosomes (APs) and autolysosomes (ALs) were reduced in the gastrocnemius (Gastroc) muscles of ATL-III-treated rats under transmission electron microscopy (TEM) together with the downregulation of LC3-II and upregulation of p62 according to Western blotting. This evidence indicated that ATL-III improved skeletal muscle atrophy and alleviated oxidative stress and autophagy in CKD rats. Furthermore, ATL-III could also increase the protein levels of p-PI3K, p-AKT, and p-mTOR in skeletal muscles in CKD rats. To further reveal the relevant mechanism, the oxidative stress-mediated PI3K/AKT/mTOR pathway was assessed, which showed that a reduced expression of p-PI3K, p-AKT, and p-mTOR in C2C12 myoblast atrophy induced by TNF-α could be upregulated by ATL-III; however, after the overexpression of Nox2 to increase ROS production, the attenuated effect was reversed. Our findings indicated that ATL-III is a potentially protective drug against muscle wasting via activation of the oxidative stress-mediated PI3K/AKT/mTOR pathway.

Hydroxy-α-sanshool Possesses Protective Potentials on H2O2-Stimulated PC12 Cells by Suppression of Oxidative Stress-Induced Apoptosis through Regulation of PI3K/Akt Signal Pathway

“…Currently, increasing evidences have suggested that the PI3K/AKT signal pathway plays a crucial role in cell survival and development as well as ROS-induced cell apoptosis [40,41]. In addition, the PI3K/AKT pathway shows significant antioxidant activity in central and peripheral neurons and can be considered a potential therapeutic target for neurodegenerative diseases, participating in the cellular protective mechanism of ROS-induced cell damage [39].…”

Potential mechanisms of Chinese Herbal Medicine that implicated in the treatment of COVID-19 related renal injury

“…Bai Zhu is commonly used to invigorate the spleen to regulate water in kidney, according to CHM theory. Studies have demonstrated that Atractylodes macrocephala can reduce chronic kidney disease-induced inflammation and muscle atrophy by inhibiting the PI3K-Akt pathway ( Wang et al, 2019a , Wang et al, 2019b ). At the same time, it can reduce the production of proinflammatory mediators NO, reduce the levels of TNF and IL, and then relieve the damage of renal cells ( Ishii et al, 2020 ).…”

“…In addition, for drug-induced renal injury, it has been shown that Huang Qi can protect against gentamicin-induced renal injury by inhibiting oxidative stress response and inflammatory factors ( Wang et al, 2019a , Wang et al, 2019b ). The triterpenoids extracted from Fu Ling have protective effects on cisplatin nephrotoxicity, and the mechanism is related to the anti-apoptotic activity of the ingredients ( Lee et al, 2017 ).…”

Effect of Eriocalyxin B on prostatic inflammation and pelvic pain in a mouse model of experimental autoimmune prostatitis

“…[36][37][38] Chrysin reportedly inhibited inflammation and decreased IL-1β, TNF-α, and IL-6 levels by activating the PI3K/AKT/ mTOR pathway. 38 Wang et al 39 The phosphorylation of IκBa by IKK triggers a signal for the ubiquitination and degradation of IκBa followed by activation of NF-κB. 40 Activation of NF-κB by IKK also occurs in association with reactive oxygen species (ROS) produced by NADPH oxidase in response to activation of receptors, such as IL-1 or TNF.…”