Salvianolic Acid C Protects against Cisplatin-Induced Acute Kidney Injury through Attenuation of Inflammation, Oxidative Stress and Apoptotic Effects and Activation of the CaMKK–AMPK–Sirt1-Associated Signaling Pathway in Mouse Models

Abstract

Acute kidney injury (AKI) is a sudden reduction in kidney activity and has a high mortality rate. Salvianolic acid C (SAC), one of the main polyphenolic components of Salvia miltiorrhiza, displays significant pharmacologically active effects. An animal model of cisplatin-induced kidney injury was used to study the potential of SAC to improve AKI. First, SAC was administered intraperitoneally in mice for 10 consecutive days, and then cisplatin was administered intraperitoneally on day 7 to establish a nephrotoxicity mouse model. SAC mitigated renal histological changes, blood creatinine (CRE) and blood urea nitrogen (BUN) production and the levels of inflammatory mediators in the cisplatin-induced AKI. Furthermore, malondialdehyde (MDA) levels were reduced and glutathione (GSH) was increased after intraperitoneal injection (i.p.) administration of SAC. In addition, based on Western blot data, SAC reduced the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation in mouse renal tissues. Finally, SAC diminished the level of TLR-4 expression and enhanced the production of several antioxidative enzymes (superoxidase dismutase (SOD1), glutathione peroxidase (GPx3), catalase, nuclear-factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1)), Sirtuin 1 (Sirt1), p-AMP-activated protein kinase (AMPK) and p-Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). In addition, Sirt1 inhibition (EX 527) inverted the effect of SAC against cisplatin-induced nephrotoxicity. Collectively, SAC provides a therapeutic target with promising clinical potential after cisplatin treatment by attenuating oxidative stress and inflammation.

TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity

“…In this study, the Cp-injected rats demonstrated deliberate oxidative stress in the kidneys indicated by a significant increase in lipid peroxidation along with the depletion of total antioxidants levels and reduced catalase activity. These findings were consistent with those reported by previous studies [ 27 , 51 , 52 , 53 ]. ROS can activate both inflammatory and apoptotic pathways.…”

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats

“…In the current work, cisplatin caused downregulation of ovarian AMPK mRNA expression compared to the control group. Cisplatin has been reported to cause renal injury through the downregulation of AMPK expression [86,87]. In contrast, melatonin co-administration with cisplatin increased the expression of AMPK mRNA in the ovarian tissues.…”

Identification and validation of hub genes in drug induced acute kidney injury basing on integrated transcriptomic analysis

“…Activation of TLR4 on renal parenchymal cells may activate the p38 MAPK pathway, leading to increased production of inflammatory cytokines such as TNF-α and subsequent renal injury ( 39 ). Salvianolic acid C ( 40 ), Cordyceps cicadae Mycelia ( 41 ) reduce the expression level of TLR-4 and enhance several antioxidant enzymes (superoxide dismutase and glutathione peroxidase) to alleviate cisplatin induced AKI. Consistent with the above results, our results showed that TLR4 mRNA levels were significantly elevated in cells and mouse models of DI-AKI.…”