Delineation of Renal Protein Profiles in Aristolochic Acid I-induced Nephrotoxicity in Mice by Label-free Quantitative Proteomics

Overview

Journal Front Pharmacol

Date 2024 May 24

PMID 38783935

Authors

Xinhui Liu

Shanshan Wu

Yu Peng

Liwen Gao

Xi Huang

Ruyu Deng

Jiandong Lu

Affiliations

Soon will be listed here.

Abstract

Aristolochic acid nephropathy (AAN) is a kidney injury syndrome caused by aristolochic acids exposure. Our study used label-free quantitative proteomics to delineate renal protein profiles and identify key proteins after exposure to different doses of aristolochic acid I (AAI). Male C57BL/6 mice received AAI (1.25 mg/kg/d, 2.5 mg/kg/d, or 5 mg/kg/d) or vehicle for 5 days. The results showed that AAI induced dose-dependent nephrotoxicity. Differences in renal protein profiles between the control and AAI groups increased with AAI dose. Comparing the control with the low-, medium-, and high-dose AAI groups, we found 58, 210, and 271 differentially expressed proteins, respectively. Furthermore, protein-protein interaction network analysis identified acyl-CoA synthetase medium-chain family member 3 (Acsm3), cytochrome P450 family 2 subfamily E member 1 (Cyp2e1), microsomal glutathione S-transferase 1 (Mgst1), and fetuin B (Fetub) as the key proteins. Proteomics revealed that AAI decreased Acsm3 and Cyp2e1 while increasing Mgst1 and Fetub expression in mice kidneys, which was further confirmed by Western blotting. Collectively, in AAI-induced nephrotoxicity, renal protein profiles were dysregulated and exacerbated with increasing AAI dose. Acsm3, Cyp2e1, Mgst1, and Fetub may be the potential therapeutic targets for AAN.

References

Johansson K, Ahlen K, Rinaldi R, Sahlander K, Siritantikorn A, Morgenstern R . Microsomal glutathione transferase 1 in anticancer drug resistance. Carcinogenesis. 2006; 28(2):465-70. DOI: 10.1093/carcin/bgl148. View

Gorigk S, Ouwens D, Kuhn T, Altenhofen D, Binsch C, Damen M . Nudix hydrolase NUDT19 regulates mitochondrial function and ATP production in murine hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids. 2022; 1867(6):159153. DOI: 10.1016/j.bbalip.2022.159153. View

Pozdzik A, Salmon I, Husson C, Decaestecker C, Rogier E, Bourgeade M . Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy. Nephrol Dial Transplant. 2008; 23(8):2480-91. DOI: 10.1093/ndt/gfn140. View

Kang H, Ahn S, Choi P, Ko Y, Han S, Chinga F . Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2014; 21(1):37-46. PMC: 4444078. DOI: 10.1038/nm.3762. View

Anger E, Yu F, Li J . Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches. Int J Mol Sci. 2020; 21(3). PMC: 7043226. DOI: 10.3390/ijms21031157. View

Yang B, Xie Y, Guo M, Rosner M, Yang H, Ronco C . Nephrotoxicity and Chinese Herbal Medicine. Clin J Am Soc Nephrol. 2018; 13(10):1605-1611. PMC: 6218812. DOI: 10.2215/CJN.11571017. View

Liu H, Baliga R . Cytochrome P450 2E1 null mice provide novel protection against cisplatin-induced nephrotoxicity and apoptosis. Kidney Int. 2003; 63(5):1687-96. DOI: 10.1046/j.1523-1755.2003.00908.x. View

Johansson K, Jarvliden J, Gogvadze V, Morgenstern R . Multiple roles of microsomal glutathione transferase 1 in cellular protection: a mechanistic study. Free Radic Biol Med. 2010; 49(11):1638-45. DOI: 10.1016/j.freeradbiomed.2010.08.013. View

Luciano R, Perazella M . Aristolochic acid nephropathy: epidemiology, clinical presentation, and treatment. Drug Saf. 2014; 38(1):55-64. DOI: 10.1007/s40264-014-0244-x. View

10.

Bennett M, Devarajan P . The future role of proteomics in the understanding of acute kidney injury. Expert Rev Proteomics. 2018; 15(3):191-192. PMC: 6701839. DOI: 10.1080/14789450.2018.1443007. View

11.

Kralisch S, Hoffmann A, Lossner U, Kratzsch J, Bluher M, Stumvoll M . Regulation of the novel adipokines/ hepatokines fetuin A and fetuin B in gestational diabetes mellitus. Metabolism. 2017; 68:88-94. DOI: 10.1016/j.metabol.2016.11.017. View

12.

Cortes A, Gonsalez S, Rioja L, Oliveira S, Santos A, Prieto M . Protective outcomes of low-dose doxycycline on renal function of Wistar rats subjected to acute ischemia/reperfusion injury. Biochim Biophys Acta Mol Basis Dis. 2017; 1864(1):102-114. PMC: 5705293. DOI: 10.1016/j.bbadis.2017.10.005. View

13.

Wang S, Song R, Wang Z, Jing Z, Wang S, Ma J . S100A8/A9 in Inflammation. Front Immunol. 2018; 9:1298. PMC: 6004386. DOI: 10.3389/fimmu.2018.01298. View

14.

Brautigam L, Zhang J, Dreij K, Spahiu L, Holmgren A, Abe H . MGST1, a GSH transferase/peroxidase essential for development and hematopoietic stem cell differentiation. Redox Biol. 2018; 17:171-179. PMC: 6006721. DOI: 10.1016/j.redox.2018.04.013. View

15.

Wang Z, Shah S, Liu H, Baliga R . Inhibition of cytochrome P450 2E1 and activation of transcription factor Nrf2 are renoprotective in myoglobinuric acute kidney injury. Kidney Int. 2014; 86(2):338-49. DOI: 10.1038/ki.2014.65. View

16.

Meyer C, Nadkarni V, Stumvoll M, Gerich J . Human kidney free fatty acid and glucose uptake: evidence for a renal glucose-fatty acid cycle. Am J Physiol. 1997; 273(3 Pt 1):E650-4. DOI: 10.1152/ajpendo.1997.273.3.E650. View

17.

Manikandan P, Nagini S . Cytochrome P450 Structure, Function and Clinical Significance: A Review. Curr Drug Targets. 2017; 19(1):38-54. DOI: 10.2174/1389450118666170125144557. View

18.

Chen J, Luo P, Wang C, Yang C, Bai Y, He X . Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy. JCI Insight. 2022; 7(16). PMC: 9462482. DOI: 10.1172/jci.insight.157360. View

19.

Tang D, Kang R . SQSTM1 is a therapeutic target for infection and sterile inflammation. Cytokine. 2023; 169:156317. DOI: 10.1016/j.cyto.2023.156317. View

20.

Wu W, Liu F, Wu K, Chen Y, Wu H, Dai G . Lon Peptidase 2, Peroxisomal (LONP2) Contributes to Cervical Carcinogenesis via Oxidative Stress. Med Sci Monit. 2018; 24:1310-1320. PMC: 5846714. DOI: 10.12659/msm.908966. View