Trimethylamine N-Oxide Induces Renal Fibrosis Through the PI3K/AKT/SREBP1 Pathway

CHEN Jing; HUANG Yinghui; ZHAO Jinghong

doi:10.12182/20231160106

Volume 54 Issue 6

Dec. 2023

Turn off MathJax

Article Contents

Abstract

References

JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCES) > 2023 > 54(6): 1105-1111. > DOI: 10.12182/20231160106

CHEN Jing, HUANG Yinghui, ZHAO Jinghong. Trimethylamine N-Oxide Induces Renal Fibrosis Through the PI3K/AKT/SREBP1 Pathway[J]. Journal of Sichuan University (Medical Sciences), 2023, 54(6): 1105-1111. DOI: 10.12182/20231160106

Citation:

PDF (1053 KB)

Trimethylamine N-Oxide Induces Renal Fibrosis Through the PI3K/AKT/SREBP1 Pathway

Department of Nephrology, Second Affiliated Hospital, Army Medical University, Chongqing 400037, China

More Information

Corresponding author:
ZHAO Jinghong, E-mail: zhaojh@tmmu.edu.cn
Received Date: September 26, 2023
Revised Date: November 01, 2023
Available Online: December 19, 2023
Published Date: December 24, 2023

Abstract

Abstract

Objective To investigate the role and mechanism of trimethylamine N-oxide (TMAO), a uremic toxin, in renal fibrosis.
Methods A total of 20 male BALB/c mice were randomly and evenly assigned to a Control group and a TMAO group. Mice in the Control group received intraperitoneal injection of normal saline, while mice in the TMAO group received intraperitoneal injection of TMAO (20 mg/[kg·d]). The injection was given once a day for 8 weeks. Histopathology and fibrosis of kidney were observed by H&E staining and Masson staining. Immunohistochemistry was performed to determine the levels of alpha smooth muscle actin (α-SMA), recombinant human fibronectin fragment (Fibronectin), and sterol-regulatory element binding protein 1 (SREBP1). Western blot was performed to determine α-SMA, SREBP1, phosphatidylinositol 3 kinase (PI3K), phospho-phosphatidylinositol 3 kinase (p-PI3K), protein kinase B (PKB, also known as AKT), and phospho-AKT (p-AKT) protein levels. HK2 cells were treated with SREBP1 small interfering RNA (siRNA) and PI3K/AKT inhibitor, respectively, and the reversal of the effects of TMAO was examined.
Results Animal experiments showed that, compared with the Control group, the mice treated with TMAO experienced pathological damage and fibrosis of the kidney tissue and the expression levels of fibrosis markers, α-SMA and Fibronectin, in the kidney were increased (all P<0.05). According to the findings from further investigation, the TMAO-treatment group showed increased expression of SREBP1 and an up-regulation of PI3K phosphorylation ratio and AKT phosphorylation ratio compared with those of the Control group (all P<0.05). Cell experiments produced results similar to those of the animal experiment. After siRNA interference with SREBP1 expression, the expression levels of fibrosis marker proteins decreased (P<0.05). Besides, the high expression of SREBP1 caused by TMAO was inhibited after HK2 cells were incubated with LY294002, a PI3K-AKT pathway inhibitor (P<0.05).
Conclusion TMAO may induce renal fibrosis by promoting the PI3K/AKT/SREBP1 pathway.
- Trimethylamine N-oxide,
- Renal fibrosis,
- PI3K/AKT pathway,
- SREBP1

FullText(HTML)

References (24)

References

[1]	HUMPHREYS B D. Mechanisms of renal fibrosis. Annu Rev Physiol,2018,80(1): 309–326. DOI: 10.1146/annurev-physiol-022516-034227
[2]	RUIZ-ORTEGA M, LAMAS S, ORTIZ A. Antifibrotic agents for the management of CKD: a review. Am J Kidney Dis,2022,80(2): 251–263. DOI: 10.1053/j.ajkd.2021.11.010
[3]	ZHOU W, WU W H, SI Z L, et al. The gut microbe Bacteroides fragilis ameliorates renal fibrosis in mice. Nat Commun,2022,13(1): 6081. DOI: 10.1038/s41467-022-33824-6
[4]	CHEN J, TANG Y, ZHONG Y, et al. P2Y12 inhibitor clopidogrel inhibits renal fibrosis by blocking macrophage-to-myofibroblast transition. Mol Ther ISSN,2022,30(9): 3017–3033. DOI: 10.1016/j.ymthe.2022.06.019
[5]	GENG X Q, MA A, HE J Z, et al. Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways. Acta Pharmacol Sin,2020,41(5): 670–677. DOI: 10.1038/s41401-019-0324-7
[6]	LI S, QIU B, LU H, et al. Hyperhomocysteinemia accelerates acute kidney injury to chronic kidney disease progression by downregulating heme oxygenase-1 expression. Antioxid Redox Signal,2019,30(13): 1635–1650. DOI: 10.1089/ars.2017.7397
[7]	NAKANO T, WATANABE H, IMAFUKU T, et al. Indoxyl sulfate contributes to mTORC1-induced renal fibrosis via the OAT/NADPH oxidase/ROS pathway. Toxins,2021,13(12): 909. DOI: 10.3390/toxins13120909
[8]	SUN B, WANG X, LIU X, et al. Hippuric acid promotes renal fibrosis by disrupting redox homeostasis via facilitation of NRF2-KEAP1-CUL3 interactions in chronic kidney disease. Antioxidants,2020,9(9): 783. DOI: 10.3390/antiox9090783
[9]	WANG S, ZUO A, JIANG W, et al. JMJD1A/NR4A1 signaling regulates the procession of renal tubular epithelial interstitial fibrosis induced by AGEs in HK-2. Front Med,2021,8: 807694. DOI: 10.3389/fmed.2021.807694
[10]	RAYEGO-MATEOS S, VALDIVIELSO J M. New therapeutic targets in chronic kidney disease progression and renal fibrosis. Expert Opin Ther Targets,2020,24(7): 655–670. DOI: 10.1080/14728222.2020.1762173
[11]	WU K, YUAN Y, YU H, et al. The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice. Blood,2020,136(4): 501–515. DOI: 10.1182/blood.2019003990
[12]	KIM S J, ZHANG X, CHO S B, et al. Uremic solutes of indoxyl sulfate and p-cresol enhance protease-activated receptor-2 expression in vitro and in vivo in keratinocytes. Hum Exp Toxicol,2021,40(1): 113–123. DOI: 10.1177/0960327120945758
[13]	JIANG S, SHUI Y, CUI Y, et al. Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin Ⅱ-induced hypertension. Redox Biol,2021,46: 102115. DOI: 10.1016/j.redox.2021.102115
[14]	CHU H, DU C, YANG Y, et al. MC-LR aggravates liver lipid metabolism disorders in obese mice fed a high-fat diet via PI3K/AKT/mTOR/SREBP1 signaling pathway. Toxins,2022,14(12): 833. DOI: 10.3390/toxins14120833
[15]	ZHOU Z, LIANG S, ZHOU Z, et al. TGF-β1 promotes SCD1 expression via the PI3K-Akt-mTOR-SREBP1 signaling pathway in lung fibroblasts. Respir,2023,24(1): 8. DOI: 10.1186/s12931-023-02313-9
[16]	SHI H H, CHEN L P, WANG C C, et al. Docosahexaenoic acid-acylated curcumin diester alleviates cisplatin-induced acute kidney injury by regulating the effect of gut microbiota on the lipopolysaccharide- and trimethylamine-N-oxide-mediated PI3K/Akt/NF-κB signaling pathway in mice. Food Funct,2022,13(11): 6103–6117. DOI: 10.1039/d1fo04178a
[17]	LI D, KE Y, ZHAN R, et al. Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell,2018,17(4): e12768. DOI: 10.1111/acel.12768
[18]	ZENG Y, GUO M, FANG X, et al. Gut microbiota-derived trimethylamine N-oxide and kidney function: a systematic review and meta-analysis. Adv Nutr,2021,12(4): 1286–1304. DOI: 10.1093/advances/nmab010
[19]	FANG Q, ZHENG B, LIU N, et al. Trimethylamine N-oxide exacerbates renal inflammation and fibrosis in rats with diabetic kidney disease. Front Physiol,2021,12: 682482. DOI: 10.3389/fphys.2021.682482
[20]	GUPTA N, BUFFA J A, ROBERTS A B, et al. Targeted inhibition of gut microbial trimethylamine n-oxide production reduces renal tubulointerstitial fibrosis and functional impairment in a murine model of chronic kidney disease. Arterioscl Throm Vas,2020,40(5): 1239–1255. DOI: 10.1161/ATVBAHA.120.314139
[21]	LIN Y C, WU M S, LIN Y F, et al. Nifedipine modulates renal lipogenesis via the AMPK-SREBP transcriptional pathway. Int J Mol Sci,2019,20(7): 1570. DOI: 10.3390/ijms20071570
[22]	GAI Z, WANG T, VISENTIN M, et al. Lipid accumulation and chronic kidney disease. Nutrients,2019,11(4): 722. DOI: 10.3390/nu11040722
[23]	DOROTEA D, KOYA D, HA H. Recent insights into SREBP as a direct mediator of kidney fibrosis via lipid-independent pathways. Front Pharmacol,2020,11: 265. DOI: 10.3389/fphar.2020.00265
[24]	KAPETANAKI S, KUMAWAT A K, PERSSON K, et al. The fibrotic effects of TMAO on human renal fibroblasts is mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR pathway. Int J Mol Sci,2021,22(21): 11864. DOI: 10.3390/ijms222111864

OPEN ACCESS This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International license (CC BY-NC 4.0). In other words, the full-text content of the journal is made freely available for third-party users to copy and redistribute in any medium or format, and to remix, transform, and build upon the content of the journal. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may not use the content of the journal for commercial purposes. For more information about the license, visit https://creativecommons.org/licenses/by-nc/4.0

Relative Articles

Supplements (0)

Cited By

Get Citation

PDF

XML

Article views (1738) PDF downloads (62)

Trimethylamine N-Oxide Induces Renal Fibrosis Through the PI3K/AKT/SREBP1 Pathway

Abstract

References

Catalog

Export File

Citation

Format

Content