Deficiency of flavin-containing monooxygenase 3 protects kidney function after ischemia-reperfusion in mice.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
27 Aug 2024
27 Aug 2024
Historique:
received:
11
01
2024
accepted:
09
08
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
27
8
2024
Statut:
epublish
Résumé
The kidney is vulnerable to ischemia and reperfusion (I/R) injury that can be fatal after major surgery. Currently, there are no effective treatments for I/R-induced kidney injury. Trimethylamine N-oxide (TMAO) is a gut-derived metabolite linked to many diseases, but its role in I/R-induced kidney injury remains unclear. Here, our clinical data reveals an association between preoperative systemic TMAO levels and postoperative kidney injury in patients after post-cardiopulmonary bypass surgery. By genetic deletion of TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) and dietary supplementation of choline to modulate TMAO levels, we found that TMAO aggravated acute kidney injury through the triggering of endoplasmic reticulum (ER) stress and worsened subsequent renal fibrosis through TGFβ/Smad signaling activation. Together, our study underscores the negative role of TMAO in I/R-induced kidney injury and highlights the therapeutic potential through the modulation of TMAO levels by targeting FMO3, thereby mitigating acute kidney injury and preventing subsequent renal fibrosis.
Identifiants
pubmed: 39191965
doi: 10.1038/s42003-024-06718-0
pii: 10.1038/s42003-024-06718-0
doi:
Substances chimiques
dimethylaniline monooxygenase (N-oxide forming)
EC 1.14.13.8
Oxygenases
EC 1.13.-
trimethyloxamine
FLD0K1SJ1A
Methylamines
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1054Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 92368112
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81921006
Informations de copyright
© 2024. The Author(s).
Références
Susantitaphong, P. et al. World incidence of AKI: a meta-analysis. Clin. J. Am. Soc. Nephrol. 8, 1482–1493 (2013).
pubmed: 23744003
pmcid: 3805065
doi: 10.2215/CJN.00710113
Bedford, M., Farmer, C., Levin, A., Ali, T. & Stevens, P. Acute kidney injury and CKD: chicken or egg? Am. J. Kidney Dis. 59, 485–491 (2012).
pubmed: 22444492
doi: 10.1053/j.ajkd.2011.09.010
Ronco, C., Bellomo, R. & Kellum, J. A. Acute kidney injury. Lancet 394, 1949–1964 (2019).
pubmed: 31777389
doi: 10.1016/S0140-6736(19)32563-2
Molitoris, B. A. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J. Clin. Invest. 124, 2355–2363 (2014).
pubmed: 24892710
pmcid: 4089444
doi: 10.1172/JCI72269
Oh, C. J. et al. Inhibition of pyruvate dehydrogenase kinase 4 ameliorates kidney ischemia–reperfusion injury by reducing succinate accumulation during ischemia and preserving mitochondrial function during reperfusion. Kidney Int. 104, 724–739 (2023).
pubmed: 37399974
doi: 10.1016/j.kint.2023.06.022
Ishani, A. et al. Acute kidney injury increases risk of ESRD among elderly. J. Am. Soc. Nephrol. 20, 223–228 (2009).
pubmed: 19020007
pmcid: 2615732
doi: 10.1681/ASN.2007080837
Amdur, R. L., Chawla, L. S., Amodeo, S., Kimmel, P. L. & Palant, C. E. Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis. Kidney Int. 76, 1089–1097 (2009).
pubmed: 19741590
doi: 10.1038/ki.2009.332
Ramezani, A. et al. Role of the gut microbiome in uremia: a potential therapeutic target. Am. J. Kidney Dis. J. Natl Kidney Found. 67, 483–498 (2016).
doi: 10.1053/j.ajkd.2015.09.027
Tang, W. H. et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ. Res. 116, 448–455 (2015).
pubmed: 25599331
doi: 10.1161/CIRCRESAHA.116.305360
Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med 19, 576–585 (2013).
pubmed: 23563705
pmcid: 3650111
doi: 10.1038/nm.3145
Gatarek, P. & Kaluzna-Czaplinska, J. Trimethylamine N-oxide (TMAO) in human health. EXCLI J. 20, 301–319 (2021).
pubmed: 33746664
pmcid: 7975634
Koukouritaki, S. B., Simpson, P., Yeung, C. K., Rettie, A. E. & Hines, R. N. Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression. Pediatr. Res. 51, 236–243 (2002).
pubmed: 11809920
doi: 10.1203/00006450-200202000-00018
Kaysen, G. A. et al. Associations of trimethylamine N-oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis. J. Ren. Nutr. 25, 351–356 (2015).
pubmed: 25802017
pmcid: 4469547
doi: 10.1053/j.jrn.2015.02.006
Stubbs, J. R. et al. Serum triethylamine N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J. Am. Soc. Nephrol. 27, 305–313 (2016).
pubmed: 26229137
doi: 10.1681/ASN.2014111063
Shafi, T. et al. Trimethylamine N-oxide and cardiovascular events in hemodialysis patients. J. Am. Soc. Nephrol. 28, 321–331 (2017).
pubmed: 27436853
doi: 10.1681/ASN.2016030374
Massoth, C., Zarbock, A. & Meersch, M. Acute kidney injury in cardiac surgery. Crit. Care Clin. 37, 267–278 (2021).
pubmed: 33752855
doi: 10.1016/j.ccc.2020.11.009
Lannemyr, L. et al. Effects of cardiopulmonary bypass on renal perfusion, filtration, and oxygenation in patients undergoing cardiac surgery. Anesthesiology 126, 205–213 (2017).
pubmed: 27906706
doi: 10.1097/ALN.0000000000001461
Ranucci, M. et al. Oxygen delivery during cardiopulmonary bypass and acute renal failure after coronary operations. Ann. Thorac. Surg. 80, 2213–2220 (2005).
pubmed: 16305874
doi: 10.1016/j.athoracsur.2005.05.069
Bennett, B. J. et al. Trimethylamine N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17, 49–60 (2013).
pubmed: 23312283
pmcid: 3771112
doi: 10.1016/j.cmet.2012.12.011
Cheruku, S. R., Raphael, J., Neyra, J. A. & Fox, A. A. Acute kidney injury after cardiac surgery: prediction, prevention, and management. Anesthesiology 139, 880–898 (2023).
pubmed: 37812758
doi: 10.1097/ALN.0000000000004734
Chaturvedi, S., Farmer, T. & Kapke, G. F. Assay validation for KIM-1: human urinary renal dysfunction biomarker. Int J. Biol. Sci. 5, 128–134 (2009).
pubmed: 19173034
pmcid: 2631222
doi: 10.7150/ijbs.5.128
Du, H. et al. Establishment of epithelial inflammatory injury model using adult kidney organoids. Life Med. https://doi.org/10.1093/lifemedi/lnae022 (2024).
Xu, L., Sharkey, D. & Cantley, L. G. Tubular GM-CSF promotes late MCP-1/CCR2-mediated fibrosis and inflammation after ischemia/reperfusion injury. J. Am. Soc. Nephrol. 30, 1825–1840 (2019).
pubmed: 31315923
pmcid: 6779361
doi: 10.1681/ASN.2019010068
Yang, B. et al. Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia–reperfusion injury. J. Am. Soc. Nephrol. 29, 1900–1916 (2018).
pubmed: 29925521
pmcid: 6050936
doi: 10.1681/ASN.2017050581
Zhou, X. et al. Tubular cell-derived exosomal miR-150-5p contributes to renal fibrosis following unilateral ischemia–reperfusion injury by activating fibroblast in vitro and in vivo. Int J. Biol. Sci. 17, 4021–4033 (2021).
pubmed: 34671216
pmcid: 8495396
doi: 10.7150/ijbs.62478
Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. TGF-beta: the master regulator of fibrosis. Nat. Rev. Nephrol. 12, 325–338 (2016).
pubmed: 27108839
doi: 10.1038/nrneph.2016.48
Rhee, E. P. et al. A combined epidemiologic and metabolomic approach improves CKD prediction. J. Am. Soc. Nephrol. 24, 1330–1338 (2013).
pubmed: 23687356
pmcid: 3736702
doi: 10.1681/ASN.2012101006
Kapetanaki, S., Kumawat, A. K., Persson, K. & Demirel, I. 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. https://doi.org/10.3390/ijms222111864 (2021).
Seldin, M. M. et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-kappaB. J. Am. Heart Assoc. https://doi.org/10.1161/JAHA.115.002767 (2016).
Kong, L. et al. Trimethylamine N-oxide impairs beta-cell function and glucose tolerance. Nat. Commun. 15, 2526 (2024).
pubmed: 38514666
pmcid: 10957989
doi: 10.1038/s41467-024-46829-0
Xiong, Z. et al. The gut microbe-derived metabolite trimethylamine-N-oxide induces aortic valve fibrosis via PERK/ATF-4 and IRE-1alpha/XBP-1s signaling in vitro and in vivo. Atherosclerosis 391, 117431 (2024).
pubmed: 38408412
doi: 10.1016/j.atherosclerosis.2023.117431
Li, J. et al. Trimethylamine N-oxide induces osteogenic responses in human aortic valve interstitial cells in vitro and aggravates aortic valve lesions in mice. Cardiovasc. Res. 118, 2018–2030 (2022).
pubmed: 34352088
doi: 10.1093/cvr/cvab243
Wang, F. et al. Transplantation of fecal microbiota from APP/PS1 mice and Alzheimer’s disease patients enhanced endoplasmic reticulum stress in the cerebral cortex of wild-type mice. Front. Aging Neurosci. 14, 858130 (2022).
pubmed: 35966768
pmcid: 9367971
doi: 10.3389/fnagi.2022.858130
Govindarajulu, M. et al. Gut metabolite TMAO induces synaptic plasticity deficits by promoting endoplasmic reticulum stress. Front. Mol. Neurosci. 13, 138 (2020).
pubmed: 32903435
pmcid: 7437142
doi: 10.3389/fnmol.2020.00138
Lattard, V., Lachuer, J., Buronfosse, T., Garnier, F. & Benoit, E. Physiological factors affecting the expression of FMO1 and FMO3 in the rat liver and kidney. Biochem. Pharm. 63, 1453–1464 (2002).
pubmed: 11996886
doi: 10.1016/S0006-2952(02)00886-9
Qiu, L. et al. Beyond UPR: cell-specific roles of ER stress sensor IRE1alpha in kidney ischemic injury and transplant rejection. Kidney Int. 104, 463–469 (2023).
pubmed: 37391039
doi: 10.1016/j.kint.2023.06.016
Yang, W. et al. Gut microbe-derived metabolite trimethylamine N-oxide accelerates fibroblast-myofibroblast differentiation and induces cardiac fibrosis. J. Mol. Cell Cardiol. 134, 119–130 (2019).
pubmed: 31299216
doi: 10.1016/j.yjmcc.2019.07.004
Consortium, A. B. et al. A biomarker framework for cardiac aging: the Aging Biomarker Consortium consensus statement. Life Med. https://doi.org/10.1093/lifemedi/lnad035 (2023).
Livingston, M. J. et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy 19, 256–277 (2023).
pubmed: 35491858
doi: 10.1080/15548627.2022.2072054
Humphreys, B. D. Mechanisms of renal fibrosis. Annu Rev. Physiol. 80, 309–326 (2018).
pubmed: 29068765
doi: 10.1146/annurev-physiol-022516-034227
Andrikopoulos, P. et al. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide. Nat. Commun. 14, 5843 (2023).
pubmed: 37730687
pmcid: 10511707
doi: 10.1038/s41467-023-39824-4
Kim, H. J. et al. Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2alpha-ATF4 pathway. Free Radic. Biol. Med 110, 81–91 (2017).
pubmed: 28578014
doi: 10.1016/j.freeradbiomed.2017.05.026
Blohmke, C. J. et al. Atypical activation of the unfolded protein response in cystic fibrosis airway cells contributes to p38 MAPK-mediated innate immune responses. J. Immunol. 189, 5467–5475 (2012).
pubmed: 23105139
doi: 10.4049/jimmunol.1103661
Zhao, Y. S. et al. Hydrogen and oxygen mixture to improve cardiac dysfunction and myocardial pathological changes induced by intermittent hypoxia in rats. Oxid. Med Cell Longev. 2019, 7415212 (2019).
pubmed: 30984338
pmcid: 6431505
doi: 10.1155/2019/7415212
Shu, S. et al. Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis. Cell Death Dis. 12, 1016 (2021).
pubmed: 34716302
pmcid: 8556380
doi: 10.1038/s41419-021-04274-7
Khwaja, A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin. Pr. 120, c179–184 (2012).
doi: 10.1159/000339789
Fu, Y. et al. Rodent models of AKI-CKD transition. Am. J. Physiol. Ren. Physiol. 315, F1098–F1106 (2018).
doi: 10.1152/ajprenal.00199.2018
Zager, R. A., Johnson, A. C. & Becker, K. Acute unilateral ischemic renal injury induces progressive renal inflammation, lipid accumulation, histone modification, and “end-stage” kidney disease. Am. J. Physiol. Ren. Physiol. 301, F1334–1345 (2011).
doi: 10.1152/ajprenal.00431.2011
Ocque, A. J., Stubbs, J. R. & Nolin, T. D. Development and validation of a simple UHPLC-MS/MS method for the simultaneous determination of trimethylamine N-oxide, choline, and betaine in human plasma and urine. J. Pharm. Biomed. Anal. 109, 128–135 (2015).
pubmed: 25767908
doi: 10.1016/j.jpba.2015.02.040
Lee, P. Y. et al. Induced pluripotent stem cells without c-Myc attenuate acute kidney injury via downregulating the signaling of oxidative stress and inflammation in ischemia–reperfusion rats. Cell Transpl. 21, 2569–2585 (2012).
doi: 10.3727/096368912X636902
Wang, J. et al. Prophylactic supplementation with lactobacillus reuteri or its metabolite GABA protects against acute ischemic cardiac injury. Adv. Sci. 11, e2307233 (2024).
doi: 10.1002/advs.202307233
Zhang, H. et al. Prophylactic supplementation with Bifidobacterium infantis or its metabolite inosine attenuates cardiac ischemia/reperfusion injury. iMeta https://doi.org/10.1002/imt2.220 (2024).