Vaccarin alleviates cisplatin-induced acute kidney injury via decreasing NOX4-derived ROS

by Selleckchem | Jan 08 2024

Cisplatin is a chemotherapeutant widely used in treating solid tumors, with the common side effect of acute kidney injury (AKI). Developing effective useful agent for preventing or treating cisplatin-induced AKI is of great importance. In this study, we investigate the protective effect of vaccarin, a chemical entity of flavonoid glycoside, against cisplatin-induced AKI. Cisplatin-treated C57BL/6J mice and human kidney-2 (HK-2) cells were used as the model of cisplatin-induced AKI. The levels of blood urea nitrogen (BUN) and creatine (Cr) levels and periodic acid-Schiff staining (PAS) scores decreased when vaccarin was administrated. Vaccarin had no impact on renal platinum accumulation, which was detected by the ICP-MS 6 h after cisplatin injection. Moreover, vaccarin can significantly alleviate the product of reactive oxygen species and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) in cisplatin-induced AKI, both in vivo and in vitro. In addition, vaccarin decreased the receptor-interacting protein kinase 1 (RIPK1) related programmed necrosis (necroptosis), cell apoptosis (shown by the protein levels of cleaved-caspase3 and flow cytometry) and inflammation (shown by the decreased levels of NLRP3, p-P65 and the mRNA of several inflammatory factors). NOX4 inhibitor GLX351322 (GLX) and NOX4 kowndown by siRNA have equivalent protective effect of vaccarin in vitro. When vaccarin was administered together with GLX or NOX4 siRNA, this protective effect of vaccarin did not further increase, as indicating by the index of oxidative stress, cell viability, necroptosis and apoptosis. In conclusion, vaccarin can alleviate cisplatin-induced AKI via inhibiting NOX4.

Comments:

It seems like the study you've mentioned investigates the potential protective effects of vaccarin, a flavonoid glycoside, against cisplatin-induced acute kidney injury (AKI) in both mice and human kidney cells (HK-2 cells). Here's a breakdown of the findings:

1. **Effectiveness against Cisplatin-Induced AKI:** The study shows that when administered alongside cisplatin, vaccarin reduced the levels of blood urea nitrogen (BUN) and creatinine (Cr), commonly used indicators of kidney function. This suggests a potential protective effect against cisplatin-induced AKI.

2. **Impact on Renal Platinum Accumulation:** Despite its protective effects, vaccarin didn't seem to affect the accumulation of platinum in the kidneys, which is notable as cisplatin is known to cause kidney damage partly through its accumulation in renal tissues.

3. **Reduction of Reactive Oxygen Species (ROS) and NOX4 Expression:** Vaccarin demonstrated a reduction in reactive oxygen species (ROS) production and the expression of NOX4, a protein known to be involved in oxidative stress, both in the in vivo and in vitro models of AKI.

4. **Inhibition of Necroptosis, Apoptosis, and Inflammation:** Vaccarin showed effects on programmed cell death (necroptosis and apoptosis), as well as inflammation, by reducing the expression of specific proteins and mRNA associated with these processes. It reduced the levels of proteins related to necroptosis (like RIPK1) and apoptosis (cleaved-caspase3), as well as markers of inflammation (NLRP3, p-P65, and various inflammatory factors' mRNA).

5. **Role of NOX4 Inhibition:** The study suggests that the protective effect of vaccarin might be mediated through the inhibition of NOX4. When NOX4 was inhibited separately by a NOX4 inhibitor (GLX351322) or by using NOX4 siRNA, a similar protective effect was observed. Additionally, combining vaccarin with either the NOX4 inhibitor or NOX4 siRNA did not further enhance the protective effect, implying that vaccarin's mechanism might involve NOX4 inhibition.

This study sheds light on the potential of vaccarin as a protective agent against cisplatin-induced AKI by modulating oxidative stress, cell death pathways (necroptosis and apoptosis), and inflammation, possibly through the inhibition of NOX4. However, further research and clinical trials would be necessary to validate these findings and explore its application in clinical settings.