Protective Effect of Artemisia argyi and Its Flavonoid Constituents against Contrast-Induced Cytotoxicity by Iodixanol in LLC-PK1 Cells

Abstract

Preventive effects and corresponding molecular mechanisms of mugwort (Artemisia argyi) extract and its flavonoid constituents on contrast-induced nephrotoxicity were explored in the present study. We treated cultured LLC-PK1 cells with iodixanol to induce contrast-induced nephrotoxicity, and found that A. argyi extracts ameliorated the reduction in cellular viability following iodixanol treatment. The anti-apoptotic effect of A. argyi extracts on contrast-induced nephrotoxicity was mediated by the inhibition of mitogen-activated protein kinase (MAPK) phosphorylation and the activation of caspases. The flavonoid compounds isolated from A. argyi improved the viability of iodixanol-treated cells against contrast-induced nephrotoxicity. Seven compounds (1, 2, 3, 15, 16, 18, and 19) from 19 flavonoids exerted a significant protective effect. Based on the in silico oral-bioavailability and drug-likeness assessment, which evaluate the drug potential of these compounds, compound 2 (artemetin) showed the highest oral bioavailability (49.55%) and drug-likeness (0.48) values. We further investigated the compound–target–disease network of compound 2, and proliferator-activated receptor gamma (PPAR-γ) emerged as a predicted key marker for the treatment of contrast-induced nephrotoxicity. Consequently, compound 2 was the preferred candidate, and its protective effect was mediated by inhibiting the contrast-induced inflammatory response through activation of PPAR-γ and inhibition of MAPK phosphorylation and activation of caspases.

Anti-Apoptotic and Antioxidant Effects of 3-Epi-Iso-Seco-Tanapartholide Isolated from Artemisia argyi against Iodixanol-Induced Kidney Epithelial Cell Death

“…and Vaniot were obtained from Gyeongdong herbal medicine market (Seoul, South Korea) and a voucher specimen (accession number: AA1-103-130429) was stored at the Department of Biosystems and Biotechnology, Korea University, Seoul, Korea. The plant material was identified as reported previously [ 15 ].…”

“…We previously demonstrated the protective effects of an extract of A. argyi against damage induced by cisplatin and iodixanol in a renal proximal tubular LLC-PK1 cells [ 15 , 16 ]. Eupatilin isolated from A. argyi has been identified as a flavonoid that protects LLC-PK1 cells from cisplatin-induced cell damage by ameliorating apoptosis [ 16 ].…”

“…Furthermore, some phenolic compounds, as well as flavonoids isolated from A. argyi , are more effective than NAC against iodixanol-induced damage in LLC-PK1 cells. Among them, artemetin, identified as a flavonoid, and methyl caffeate, identified as a phenolic compound, are responsible for the protective activities against cytotoxicity caused by iodixanol in LLC-PK1 cells [ 15 , 17 ]. Nevertheless, more research is required to understand the biological activities of A. argyi and its phytochemical components in the treatment of nephrotoxicity.…”

Contrast Induced Acute Kidney Injury and Direct Cytotoxicity of Iodinated Radiocontrast Media on Renal Proximal Tubule Cells

“…In a similar fashion to salvianolic acid B, epigallocatechin gallate, the major antioxidant component of green tea, reduced the damage induced by iopromide in male Sprague-Dawley rats (Gao et al, 2016). A study performed by Lee et al (2018) demonstrated that the flavonoid components of Artemisia argyi, also called mugwort, completely prevented the cytotoxic effects induced by iodixanol on LLC-PK1 cells. A separate study performed by Lee et al (2016) showed that nontoxic concentrations of a-mangostin, found in mangosteen, improved the viability of iodixanol-treated LLC-PK1 cells by 90.42% against contrast-induced apoptotic damage.…”

“…Another study demonstrated that pretreating HK-2 cells with JNK inhibitor anthra[1,9-cd] pyrazol-6 (2H)-one or p38 inhibitor SB203580 significantly decreased cleaved caspase-3 activation and increased prosurvival protein bcl-2 after exposure to 200 mg×I/ml iopamidol (He et al, 2016). A more recent study on LLC-PK1 cells determined that 25 mg×I/ml of iodixanol will induce increases in activated p38 MAPK, JNK, and extracellular signalregulated kinase after 24 hours of exposure (Lee et al, 2018).…”