Chiral Amino Acids Mediate Mitochondria-Dependent Apoptosis of Human Proximal Tubular Epithelial Cells Under Oxidative Stress

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2025 Jan 8

PMID 39769204

Authors

Ying Lu

Yang Zhang

Zhaoyang Jin

Shuaishuai Cui

Li Wu

Yujian He

Affiliations

Soon will be listed here.

Abstract

Amino acids are the basic structural units of life, and their intake levels affect disease and health. In the case of renal disease, alterations in amino acid metabolism can be used not only as a clinical indicator of renal disease but also as a therapeutic strategy. However, the biological roles and molecular mechanisms of natural chiral amino acids in human proximal tubular epithelial cells (HK-2) remain unclear. In this study, cell viability assays revealed that chiral acidic amino acids (Glu and Asp) and aromatic amino acids (Trp and Phe) inhibited cell growth. The molecular mechanisms indicated that cell growth was closely related to ROS levels. Specifically, chiral Glu, Asp, Trp, and Phe induced oxidative stress and mitochondria-dependent apoptosis in HK-2 cells. This was manifested by elevated levels of intracellular ROS, 8-OHdG, and MDA, increased activities of antioxidant enzymes CAT, SOD, and GPx, decreased mitochondrial membrane potential, increased cytoplasmic Ca concentration, and cell acidification. The expression levels of apoptosis-related molecules Caspase-9, Caspase-3, Cyt-C, and Bax were increased, and the expression level of anti-apoptotic molecule Bcl-2 was decreased. Moreover, L-Glu, D-Asp, L-Trp, and D-Phe exhibited a more pronounced inhibition of cell growth and elicited more substantial alterations in gene expression compared to the other configurations.

References

Mossoba M, Sprando R . to Concordance of Toxicity Using the Human Proximal Tubule Cell Line HK-2. Int J Toxicol. 2020; 39(5):452-464. DOI: 10.1177/1091581820942534. View

Tabe Y, Lorenzi P, Konopleva M . Amino acid metabolism in hematologic malignancies and the era of targeted therapy. Blood. 2019; 134(13):1014-1023. PMC: 6764269. DOI: 10.1182/blood.2019001034. View

Foster K, Galeffi F, Gerich F, Turner D, Muller M . Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration. Prog Neurobiol. 2006; 79(3):136-71. PMC: 1994087. DOI: 10.1016/j.pneurobio.2006.07.001. View

Burlacu A . Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med. 2003; 7(3):249-57. PMC: 6741335. DOI: 10.1111/j.1582-4934.2003.tb00225.x. View

Huang Y, Mo S, Jin Y, Zheng Z, Wang H, Wu S . Ammonia-induced excess ROS causes impairment and apoptosis in porcine IPEC-J2 intestinal epithelial cells. Ecotoxicol Environ Saf. 2022; 243:114006. DOI: 10.1016/j.ecoenv.2022.114006. View

Wang Y, Chi H, Xu F, He Z, Li Z, Wu F . Cadmium chloride-induced apoptosis of HK-2 cells via interfering with mitochondrial respiratory chain. Ecotoxicol Environ Saf. 2022; 236:113494. DOI: 10.1016/j.ecoenv.2022.113494. View

Nagano T, Yamao S, Terachi A, Yarimizu H, Itoh H, Katasho R . d-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species. Life Sci Alliance. 2019; 2(1). PMC: 6339261. DOI: 10.26508/lsa.201800045. View

Jeon K, Lee S, Kwon Y, Beak J, Lee H, Ma C . Protective effect of fermented aloe extract on glutamate-induced cytotoxicity in HT22 cells. Anim Cells Syst (Seoul). 2023; 26(6):318-327. PMC: 9809408. DOI: 10.1080/19768354.2022.2147584. View

Chen A, Wang H, Zhang Y, Wang X, Yu L, Xu W . Paeoniflorin exerts neuroprotective effects against glutamate‑induced PC12 cellular cytotoxicity by inhibiting apoptosis. Int J Mol Med. 2017; 40(3):825-833. PMC: 5547935. DOI: 10.3892/ijmm.2017.3076. View

10.

Maekawa M, Okamura T, Kasai N, Hori Y, Summer K, Konno R . D-amino-acid oxidase is involved in D-serine-induced nephrotoxicity. Chem Res Toxicol. 2005; 18(11):1678-82. DOI: 10.1021/tx0500326. View

11.

Iguacel I, Schmidt J, Perez-Cornago A, Van Puyvelde H, Travis R, Stepien M . Associations between dietary amino acid intakes and blood concentration levels. Clin Nutr. 2021; 40(6):3772-3779. DOI: 10.1016/j.clnu.2021.04.036. View

12.

Zhuang J, Nie G, Yang F, Dai X, Cao H, Xing C . Cadmium induces cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells. Toxicol In Vitro. 2019; 61:104625. DOI: 10.1016/j.tiv.2019.104625. View

13.

Wang D, Wan X . Progress in research on the role of amino acid metabolic reprogramming in tumour therapy: A review. Biomed Pharmacother. 2022; 156:113923. DOI: 10.1016/j.biopha.2022.113923. View

14.

Ercal N, Luo X, Matthews R, Armstrong D . In vitro study of the metabolic effects of D-amino acids. Chirality. 1996; 8(1):24-9. DOI: 10.1002/(SICI)1520-636X(1996)8:1<24::AID-CHIR6>3.0.CO;2-G. View

15.

Lu J, Zhang Y, Dong H, Sun J, Zhu L, Liu P . New mechanism of nephrotoxicity of triptolide: Oxidative stress promotes cGAS-STING signaling pathway. Free Radic Biol Med. 2022; 188:26-34. DOI: 10.1016/j.freeradbiomed.2022.06.009. View

16.

Costa T, Burin S, Menaldo D, de Castro F, Sampaio S . Snake venom L-amino acid oxidases: an overview on their antitumor effects. J Venom Anim Toxins Incl Trop Dis. 2014; 20:23. PMC: 4060840. DOI: 10.1186/1678-9199-20-23. View

17.

Li W, Yu L, Fu B, Chu J, Chen C, Li X . Protective effects of Polygonatum kingianum polysaccharides and aqueous extract on uranium-induced toxicity in human kidney (HK-2) cells. Int J Biol Macromol. 2022; 202:68-79. DOI: 10.1016/j.ijbiomac.2022.01.043. View

18.

Li R, Dai J, Kang H . The construction of a panel of serum amino acids for the identification of early chronic kidney disease patients. J Clin Lab Anal. 2017; 32(3). PMC: 6817206. DOI: 10.1002/jcla.22282. View

19.

Ly J, Grubb D, Lawen A . The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis. 2003; 8(2):115-28. DOI: 10.1023/a:1022945107762. View

20.

GANOTE C, Peterson D, CARONE F . The nature of D-serine--induced nephrotoxicity. Am J Pathol. 1974; 77(2):269-82. PMC: 1910915. View