Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Pelargonium sidoides extract mediates nephrotoxicity through mitochondrial malfunction and cytoskeleton destabilization

  • Ju Young Lee (Animal Model Research Group, Korea Institute of Toxicology) ;
  • JuKyung Lee (Department of Medical IT Convergence, Kumoh National Institute of Technology) ;
  • Sung Ho Lee (WooGene B&G Co.,Ltd.) ;
  • Jeong Ho Hwang (Animal Model Research Group, Korea Institute of Toxicology) ;
  • Han Na Suh (Animal Model Research Group, Korea Institute of Toxicology)
  • Received : 2023.02.21
  • Accepted : 2023.04.19
  • Published : 2023.10.15
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Abstract

We investigated the cytotoxic effect of Pelargonium sidoides extract on Madin-Darby canine kidney (MDCK) cells. P. sidoides extract decreased the cell viability in a dose dependent manner (>0.2%). The extract of P. sidoides decreased the mitochondrial action potential, increased the number of reactive oxygen species (ROS) inside the cell, and caused nicotinamide adenine dinucleotide hydride (NADH) to be released, all of which are signs of mitochondrial dysfunction. The results of unbiased mRNA sequencing showed that 0.3% P. sidoides extract upregulates the apoptosis-related gene (BBC3). This finding was supported by immunoblot analysis of apoptosis signal pathways, which included Bcl-2, Bax, cytochrome C (CytC), cleaved caspase 3 (CC3), cleaved caspase 7 (CC7), cleaved caspase 9 (CC9) and cleaved PARP (CP). It is interesting to note that the elevated levels of Bax, CytC, CC3, CC7, and CC9, as well as CP, were suppressed by N-acetyl-L-cysteine (NAC) pretreatment, which points to ROS-mediated apoptosis. The small GTPases, RhoA, and Rac1/cdc42-GTP-bound active form were all lowered when P. sidoides extract was used. Also, RhoA-related cytoskeleton signals (ROCK, p-LIMK1/2, p-cofilin) and Rac1/cdc42-related signals (N-WASP, WAVE-2) were inhibited by P. sidoides extract. NAC or RhoA/Rac1/cdc42 activator pretreatment reduced P. sidoides extract-induced actin destabilization. In this work, P. sidoides extract promotes apoptosis by causing mitochondrial dysfunction and cytoskeleton disassembly.

Keywords

Acknowledgement

This work was supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIT) (grant no. CRC21021).

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