Cordyceps cicadae Mycelia Ameliorate Cisplatin-Induced Acute Kidney Injury by Suppressing the TLR4/NF-κB/MAPK and Activating the HO-1/Nrf2 and Sirt-1/AMPK Pathways in Mice.

Jeng-Shyan Deng,Shyh-Shyun Huang,Hung-Yi Chen,Chin-Chu Chen,Guan-Jhong Huang,Jung-Chun Liao,Pei-Ying Li,Li-Ya Lee,Wen-Chin Huang,Wen-Ping Jiang

doi:10.1155/2020/7912763

Abstract

Acute kidney injury (AKI) is a common clinical problem, characterized by a sudden loss of renal function, a high risk of death, and the eventual development of renal fibrosis and renal failure. Cordyceps cicadae is a traditional Chinese medicine with the potential function of kidney protection. We analyze two sputum extracts, a water extract (WCC), and an ethanol extract (ECC), to assess the potential of treating AKI in an animal model of kidney injury induced by cisplatin. A nephrotoxic mouse model was first established by intraperitoneal injection of cisplatin. Subsequently, WCC and ECC were orally administered in these mice. The results show that WCC and ECC significantly alleviated cisplatin-induced AKI renal histological changes, serum creatinine (CRE) and blood urea nitrogen (BUN) production, and the levels of NO, TNF-α, IL-1β, and IL-6. The levels of malondialdehyde (MDA) and glutathione (GSH) were suppressed by administration of WCC and ECC. However, WCC treatment prevented these changes significantly better than ECC treatment. In addition, Western blot data showed that WCC attenuated the cisplatin-induced protein expression of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS), as well as inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation in the kidney tissues. Furthermore, WCC greatly inhibited the expression of Toll-like receptor 4 (TLR4) and cisplatin-induced NF-κB activation, as well as dramatically increasing the production of antioxidative enzymes (i.e., superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1)), silent information regulator T1 (Sirt1), and p-AMP-activated protein kinase (AMPK) in the kidney tissues. In addition, we found that WCC increased the expression levels of the autophagy-related proteins LC3B and Beclin-1; proapoptotic proteins, including cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) 1; and organic anion transporters 1 (OAT1) and 3 (OAT3) in the kidney tissues. Finally, WCC, ECC, and two bioactive compounds—adenosine and N6-(2-hydroxyethyl) adenosine (HEA)—inhibited the production of nitrite oxide (NO) and intracellular reactive oxygen species (ROS) triggered by lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophages in vitro. Collectively, WCC could provide a potential therapeutic candidate for the prevention of cisplatin-induced kidney injury through the inhibition of oxidative stress and inflammation.

Highlights

Acute kidney injury (AKI) is a disease with high morbidity and mortality, which is characterized by a rapid loss of kidney function [1]
AMF is an inorganic thiophosphate cytoprotective agent, which has been evaluated as a cytoprotective agent against the toxicities of alkylating drugs and cisplatin
We examined whether pretreatment with C. cicadae mycelium extract WCC inhibited cisplatin-induced inducible nitrite oxide (NO) synthase (iNOS) and COX-2 protein expression

Summary

Introduction

Acute kidney injury (AKI) is a disease with high morbidity and mortality, which is characterized by a rapid loss of kidney function [1]. The most common causes of AKI include nephrotoxic drugs, renal ischemia-reperfusion (IR), sepsis, cardiac disease, hypertension, and diabetes mellitus. The molecular basis of cisplatin-induced renal toxicity in an animal model is not yet fully understood, current studies have suggested that it is associated with the mechanisms of oxidative stress, inflammation, hypoxia, vascular injury, and the activation of apoptotic pathways. Release of TNF-α induces other inflammatory cytokines and leads to inflammatory responses [6, 7]. These inflammatory mediators and oxidative stress can cause damage to renal tubular cells and kidney tissue. Inhibition of the inflammatory response and oxidative stress can provide a potential strategy to treat cisplatin-induced nephrotoxicity

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