Metabolomics analysis reveals a protective effect of hydroxycitric acid on calcium oxalate-induced kidney injury

Document Type : Original Article

Authors

Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, 050051, P. R. China

Abstract

Objective(s): Prior research has indicated that hydroxycitric acid (HCA) can impede the formation of calcium oxalate (CaOx) crystals, yet the specific mechanisms underlying its therapeutic effects remain unclear. In this study, we delved into the protective effects of HCA against glyoxylate-induced renal stones in rats and sought to elucidate the underlying metabolic pathways.
Materials and Methods: Forty rats were randomly assigned to five groups: control group,   model group, L-HCA-treated group, M-HCA-treated group, and H-HCA-treated group. Von Kossa staining was conducted on renal sections, and blood urea nitrogen and serum creatinine were determined by biochemical analysis. Meanwhile, body weight and urine volume were also measured. We subjected urine samples from the rats to analysis using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Next, we employed a metabolomic approach to scrutinize the metabolic profiles of each group.
Results: HCA significantly reduced blood urea nitrogen and serum creatinine, and increased body weight and urine volume. It also reduced CaOx crystal deposition. A total of 24 metabolites, exhibiting a significant reversal pattern following HCA administration, were identified as urine biomarkers indicative of HCA’s preventive effects against CaOx crystal-induced renal injury. These metabolites are primarily associated with glycine, serine, and threonine metabolism; phenylalanine metabolism; tricarboxylic acid cycle; taurine and hypotaurine metabolism; and tryptophan metabolism.
Conclusion: It was demonstrated that HCA has a protective effect against CaOx crystal-induced kidney injury in rats by modulating various metabolic pathways. Additionally, results suggest that HCA holds promise as a potential clinical therapeutic drug for both the prevention and treatment of renal stones.

Keywords

Main Subjects

References

1.Wang W, Fan J, Huang G, Li J, Zhu X, Tian Y, et al. Prevalence of kidney stones in mainland China: A systematic review. Sci Rep 2017; 7: 41630-41638.
2. Abufaraj M, Xu T, Cao C, Waldhoer T, Seitz C, D’andrea D. Prevalence and trends in kidney stone among adults in the USA: Analyses of national health and nutrition examination survey 2007-2018 data. Eur Urol Focus 2020; 7: 1468-1475.
3. Amato M, Lusini ML, Nelli F. Epidemiology of nephrolithiasis today. Urol Int 2004; 72: 1-5.
4. Howles SA, Thakker RV. Genetics of kidney stone disease. Nat Rev Urol 2020; 17: 407-421.
5. Soligo M, Morlacco A, Zattoni F, Valotto C, DE Giorgi G, Beltrami P. Metabolic syndrome and stone disease. Panminerva Med 2022; 64: 344-358.
6. Mehta M, Goldfarb DS, Nazzal L. The role of the microbiome in kidney stone formation. Int J Surg 2016; 36: 607-612. 
7. Bashir A, Zuberi SK, Musharraf B, Khan H, Ather MH. Perception of dietary influences on renal stone formation among the general population. Cureus 2022; 14: e26024-26032.
8. Rule AD, Bergstralh EJ, Melton LJ, et al. Kidney stones and the risk for chronic kidney disease. Clin. J Am Soc Nephrol 2009; 4: 804-811.
9. Baumann JM, Casella R. Prevention of calcium nephrolithiasis: The influence of diuresis on calcium oxalate crystallization in urine. Adv Prev Med 2019; 4: 1–8.
10. Spivacow FR, Del Valle EE, Lores E, Rey PG. Kidney stones: Composition, frequency and relation to metabolic diagnosis. Medicina 2016; 76: 343-348.
11. Yang B, Li J, Wang B, Wang G, Li P, Guo H, et al. Hydroxycitrate prevents calcium oxalate crystallization and kidney injury in a nephrolithiasis rat model. Urolithiasis 2022; 50: 47-53.
12. Liu X, Yuan P, Sun X, Chen Z. Hydroxycitric acid inhibits renal calcium oxalate deposition by reducing oxidative stress and inflammation. Curr Mol Med 2020; 20: 527-535.
13. Han S, Zhao C, Pokhrel G, Sun X, Chen Z, Xu H. Hydroxycitric acid tripotassium inhibits calcium oxalate crystal formation in the drosophila melanogaster model of hyperoxaluria. Med Sci Monit 2019; 25: 3662-3667.
14. Nicholson JK, Lindon JC, Holmes E. ‘Metabonomics’: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 1999; 9: 1181–1189.
15. Hollywood K, Brison DR, Goodacre R. Metabolomics: Current technologies and future trends. PROTEOMICS  2006; 6: 4716-4723.
16. Wishart DS. Emerging applications of metabolomics in drug discovery and precision medicine. Nat Rev Drug Discov 2016; 15: 473-484.
17. Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: Beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol 2016; 17: 451-459
18. Kwiatkowska E, Domański L, Dziedziejko V, Kajdy A, Stefańska K, Kwiatkowski S. The mechanism of drug nephrotoxicity and the methods for preventing kidney damage. Int J Mol Sci 2021; 22: 6109-6124.
19. Chen Y, Lu T, Pettersson-Kymmer U, Stewart ID, Butler-Laporte G, Nakanishi T, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet 2023; 55: 44-53.
20. Bujak R, Struck-Lewicka W, Markuszewski MJ, Kaliszan R. Metabolomics for laboratory diagnostics. J Pharm Biomed Anal 2015;113: 108-120. 
21. Naz S, Rivas P, Barbas C. Method validation strategies involved in non-targeted metabolomics. J Chromatogr A 2014; 1353: 99-105.
22. Zhou L, Xu JD, Zhou SS, Zhu H, Kong M, Shen H, et al. Independent or integrative processing approach of metabolite datasets from different biospecimens potentially affects metabolic pathway recognition in metabolomics. J Chromatogr A 2019; 1587: 146-154.
23. Piret SE, Guo Y, Attallah AA, Horne SJ, Zollman A, Owusu D, et al. Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans. Proc Natl Acad Sci U S A 2021 ; 118: e2024414118-2024414129.
24. Young BA, Von Korff M, Heckbert SR, Ludman EJ, Rutter C, Lin EH, et al. Association of major depression and mortality in Stage 5 diabetic chronic kidney disease. Gen Hosp Psychiatry 2010; 32: 119-124.
25. Owumi SE, Arunsi EO, Oyelere AK. The protective effect of 3-indolepropanoic acid on aflatoxin B1-induced systemic perturbation of the liver and kidney function in rats. Fundam Clin Pharmacol 2023; 37: 369-384.
26. Sun CY, Lin CJ, Pan HC, Lee CC, Lu SC, Hsieh YT, et al. Clinical association between the metabolite of healthy gut microbiota, 3-indolepropionic acid and chronic kidney disease. Clin Nutr 2019; 38: 2945-2948.
27. Gao H, Lin J, Xiong F, Yu Z, Pan S, Huang Y. Urinary microbial and metabolomic profiles in kidney stone disease. Front Cell Infect Microbiol 2022; 5: 953392-953403.
28. Lan Y, Zhu W, Duan X, Deng T, Li S, Liu Y, et al. Glycine suppresses kidney calcium oxalate crystal depositions via regulating urinary excretions of oxalate and citrate. J Cell Physiol 2021; 236: 6824-6835.
29. Jiang H, Pokhrel G, Chen Y, Wang T, Yin C, Liu J, et al. High expression of SLC26A6 in the kidney may contribute to renal calcification via an SLC26A6-dependent mechanism. Peer J 2018; 6: e5192-5208.
30. Zacchia M, Tian X, Zona E, Alpern RJ, Preisig PA. Acid stimulation of the citrate transporter NaDC-1 requires Pyk2 and ERK1/2 signaling pathways. J Am Soc Nephrol 2018; 29: 1720-1730.
31. Fernie AR, Carrari F, Sweetlove LJ. Respiratory metabolism: Glycolysis, the TCA cycle and mitochondrial electron transport. Curr Opin Plant Biol 2004 ; 7: 254-261.
32. Song CW, Kim DI, Choi S, Jang JW, Lee SY. Metabolic engineering of Escherichia coli for the production of fumaric acid. Biotechnol Bioeng 2013; 110: 2025-2034.
33. Aggarwal D, Gautam D, Sharma M, Singla SK. Bergenin attenuates renal injury by reversing mitochondrial dysfunction in ethylene glycol induced hyperoxaluric rat model. Eur J Pharmacol 2016; 791: 611–621.
34. Chaiyarit S, Thongboonkerd V. Mitochondrial dysfunction and kidney stone disease. Front Physiol 2020; 11: 566506.
35. Li CY, Deng YL, Sun HB. Taurine protected kidney from oxidative injury through mitochondrial-linked pathway in a rat model of nephrolithiasis. Urol Res 2009; 37: 211–220.
36. Baliou S, Adamaki M, Ioannou P, Pappa A, Panayiotidis M, Spandidos D, et al. Protective role of taurine against oxidative stress. Mol Med Rep 2021; 24: 605-613.
37. Kim KS, Oh DH, Kim JY, Lee BG, You JS, Chang KJ, et al. Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes. Exp Mol Med 2012; 44: 665-673.
38. Sun Y, Dai S, Tao J, Li Y, He Z, Liu Q, et al. Taurine suppresses ROS-dependent autophagy via activating Akt/mTOR signaling pathway in calcium oxalate crystals-induced renal tubular epithelial cell injury. Aging 2020; 12: 17353-17366.
39. Gao S, Yang R, Peng Z, Lu H, Li N, Ding J, et al. Metabolomics analysis for hydroxy-L-proline-induced calcium oxalate nephrolithiasis in rats based on ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry. Sci Rep 2016; 6: 30142-30153.
40. Laube N, Jansen B, Schneider A, Steffes H-J, Hesse A. Hippuric acid as a modifier of calcium oxalate crystallization. Clin Chem Lab Med 2001;39:218-222.
41. Atanassova SS, Gutzow IS. Hippuric acid as a significant regulator of supersaturation in calcium oxalate lithiasis: The physiological evidence. Biomed Res Int 2013; 2013; 1-7.
42. Penczynski KJ, Krupp D, Bring A, Bolzenius K, Remer T, Buyken AE. Relative validation of 24-h urinary hippuric acid excretion as a biomarker for dietary flavonoid intake from fruit and vegetables in healthy adolescents. Eur J Nutr 2017 ; 56: 757-766.
43. Guerra A, Folesani G, Mena P, Ticinesi A, Allegri F, Nouvenne A, et al. Hippuric acid in 24 h urine collections as a biomarker of fruits and vegetables intake in kidney stone formers. Int J Food Sci Nutr 2014; 65: 1033-1038.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 10
October 2024
Pages 1243-1250

Files

Share

How to cite

Statistics