Oxalate Regulates Crystal-cell Adhesion and Macrophage Metabolism Via JPT2/PI3K/AKT Signaling to Promote the Progression of Kidney Stones

Overview

Journal J Pharm Anal

Specialty Chemistry

Date 2024 Jul 22

PMID 39035219

Authors

Qianlin Song

Chao Song

Xin Chen

Yunhe Xiong

Ziqi He

Xiaozhe Su

Jiawei Zhou

Hu Ke

Caitao Dong

Wenbiao Liao

Sixing Yang

Affiliations

Soon will be listed here.

Abstract

Oxalate is an organic dicarboxylic acid that is a common component of plant foods. The kidneys are essential organs for oxalate excretion, but excessive oxalates may induce kidney stones. Jupiter microtubule associated homolog 2 (JPT2) is a critical molecule in Ca mobilization, and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear. This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones. Genetic approaches were used to control JPT2 expression in cells and mice, and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics. The results showed that oxalate exposure triggered the upregulation of JPT2, which is involved in nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca mobilization. Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown, and these were dominated by phosphatidylinositol 3-kinase (PI3K)/AKT signaling, respectively. Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde (SSA) in macrophages. Furthermore, JPT2 deficiency in mice inhibited kidney stones mineralization. In conclusion, this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion, and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.

References

Sheng X, Jung T, Wesson J, Ward M . Adhesion at calcium oxalate crystal surfaces and the effect of urinary constituents. Proc Natl Acad Sci U S A. 2004; 102(2):267-72. PMC: 544292. DOI: 10.1073/pnas.0406835101. View

Morgan M, Pearle M . Medical management of renal stones. BMJ. 2016; 352:i52. DOI: 10.1136/bmj.i52. View

Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X . Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019; 18(1):26. PMC: 6379961. DOI: 10.1186/s12943-019-0954-x. View

Haffner C, Becherer J, Boros E, Cadilla R, Carpenter T, Cowan D . Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors. J Med Chem. 2015; 58(8):3548-71. DOI: 10.1021/jm502009h. View

Witting C, Langman C, Assimos D, Baum M, Kausz A, Milliner D . Pathophysiology and Treatment of Enteric Hyperoxaluria. Clin J Am Soc Nephrol. 2020; 16(3):487-495. PMC: 8011014. DOI: 10.2215/CJN.08000520. View

Li Y, Lu X, Yu Z, Wang H, Gao B . Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation. Redox Biol. 2023; 61:102648. PMC: 10009205. DOI: 10.1016/j.redox.2023.102648. View

Shin S, Ibeh C, Awuah Boadi E, Choi B, Roy S, Bandyopadhyay B . Hypercalciuria switches Ca signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis. Genes Dis. 2022; 9(2):531-548. PMC: 8843860. DOI: 10.1016/j.gendis.2021.04.006. View

Liu H, Yang X, Tang K, Ye T, Duan C, Lv P . Sulforaphane elicts dual therapeutic effects on Renal Inflammatory Injury and crystal deposition in Calcium Oxalate Nephrocalcinosis. Theranostics. 2020; 10(16):7319-7334. PMC: 7330860. DOI: 10.7150/thno.44054. View

Patel S, Gunaratne G, Marchant J, Biggin P, Rahman T . NAADP receptors: A one-two. Cell Calcium. 2021; 100:102478. PMC: 9552928. DOI: 10.1016/j.ceca.2021.102478. View

10.

Liu R, Zou D, Tian M, Li K, DU J, Liu M . Effect of magnesium ammonium phosphate on the expression of adhesion molecules in sheep renal tubular epithelial cells. Res Vet Sci. 2021; 138:167-177. DOI: 10.1016/j.rvsc.2021.05.021. View

11.

Conti I, Rollins B . CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol. 2004; 14(3):149-54. DOI: 10.1016/j.semcancer.2003.10.009. View

12.

Li C, Wang L, Yuan M, Xu H, Dong J . A New Route for Indirect Mineralization of Carbon Dioxide-Sodium Oxalate as a Detergent Builder. Sci Rep. 2019; 9(1):12852. PMC: 6731234. DOI: 10.1038/s41598-019-49127-8. View

13.

Si Y, Liu L, Cheng J, Zhao T, Zhou Q, Yu J . Oral Hydrogen-Rich Water Alleviates Oxalate-Induced Kidney Injury by Suppressing Oxidative Stress, Inflammation, and Fibrosis. Front Med (Lausanne). 2021; 8:713536. PMC: 8418222. DOI: 10.3389/fmed.2021.713536. View

14.

Wang Y, Davey C, van der Maas K, van Putten R, Tietema A, Parsons J . Biodegradability of novel high T poly(isosorbide-co-1,6-hexanediol) oxalate polyester in soil and marine environments. Sci Total Environ. 2022; 815:152781. DOI: 10.1016/j.scitotenv.2021.152781. View

15.

Nio Y, Yamauchi T, Iwabu M, Okada-Iwabu M, Funata M, Yamaguchi M . Monocyte chemoattractant protein-1 (MCP-1) deficiency enhances alternatively activated M2 macrophages and ameliorates insulin resistance and fatty liver in lipoatrophic diabetic A-ZIP transgenic mice. Diabetologia. 2012; 55(12):3350-8. DOI: 10.1007/s00125-012-2710-2. View

16.

Thongprayoon C, Krambeck A, Rule A . Determining the true burden of kidney stone disease. Nat Rev Nephrol. 2020; 16(12):736-746. DOI: 10.1038/s41581-020-0320-7. View

17.

Singh S, Anshita D, Ravichandiran V . MCP-1: Function, regulation, and involvement in disease. Int Immunopharmacol. 2021; 101(Pt B):107598. PMC: 8135227. DOI: 10.1016/j.intimp.2021.107598. View

18.

Tannahill G, Curtis A, Adamik J, Palsson-McDermott E, McGettrick A, Goel G . Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013; 496(7444):238-42. PMC: 4031686. DOI: 10.1038/nature11986. View

19.

Sun A, Hinck B, Cohen B, Keslar K, Fairchild R, Monga M . Inflammatory Cytokines in the Papillary Tips and Urine of Nephrolithiasis Patients. J Endourol. 2018; 32(3):236-244. DOI: 10.1089/end.2017.0699. View

20.

Song Q, Song C, Chen X, Xiong Y, Li L, Liao W . FKBP5 deficiency attenuates calcium oxalate kidney stone formation by suppressing cell-crystal adhesion, apoptosis and macrophage M1 polarization via inhibition of NF-κB signaling. Cell Mol Life Sci. 2023; 80(10):301. PMC: 11073435. DOI: 10.1007/s00018-023-04958-7. View