Skip to main content
SpringerLink
Log in

Dimethylamine enhances platelet hyperactivity in chronic kidney disease model

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Chronic kidney disease (CKD) remains a major health threat worldwide which is associated with elevated blood level of dimethylamine (DMA) and unbalanced platelet functions. Dimethylamine, a simple aliphatic amine, is abundantly found in human urine as well as other body fluids like plasma. However, the relation between dimethylamine and platelet activation is unclear. This study aims to unravel the mechanism of DMA and platelet function in chronic kidney disease. Through in vitro platelet characterization assay and in vivo CKD mouse model, the level of DMA, platelet activity and renal function were assessed by established methods. PKCδ and its downstream kinase MEK1/2 were examined by immunoblotting analysis of human platelet extract. Rescue experiments with PKCδ inhibitor or choline deficient diet were also conducted. DMA level in plasma of mouse CKD model was elevated along with enhanced platelet activation and comprised renal function. DMA can activate platelet in vitro and in vivo. Inhibition of PKCδ could antagonize the effect of DMA on platelet activation. When choline as the dietary source of DMA was deprived from CKD mouse, the level DMA was reduced and platelet activation was attenuated. Our results demonstrate that dimethylamine could enhance platelet activation in CKD model, potentially through activation of PKCδ.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

References

  • Allen N, Barrett TJ, Guo Y, Nardi M, Ramkhelawon B, Rockman CB, Hochman JS, Berger JS (2019) Circulating monocyte-platelet aggregates are a robust marker of platelet activity in cardiovascular disease. Atherosclerosis 282:11–18

    Article  CAS  PubMed  Google Scholar 

  • Anfossi G, Russo I, Doronzo G, Pomero A, Trovati M (2010) Adipocytokines in atherothrombosis: focus on platelets and vascular smooth muscle cells. Mediators Inflamm 2010:174341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Aronov PA, Luo FJ, Plummer NS, Quan Z, Holmes S, Hostetter TH, Meyer TW (2011) Colonic contribution to uremic solutes. J Am Soc Nephrol 22(9):1769–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asatoor AM, Simenhoff ML (1965) The origin of urinary dimethylamine. Biochim Biophys Acta 111(2):384–392

    Article  CAS  PubMed  Google Scholar 

  • Baba S, Watanabe Y (1988) Fecal methylamine and dimethylamine in chronic renal failure. Anal Biochem 175(1):252–257

    Article  CAS  PubMed  Google Scholar 

  • Baber U, Mehran R, Kirtane AJ, Gurbel PA, Christodoulidis G, Maehara A, Witzenbichler B, Weisz G, Rinaldi MJ, Metzger DC, Henry TD, Cox DA et al (2015) Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the assessment of dual antiplatelet therapy with drug-eluting stents registry. Circ Cardiovasc Interv 8(6):e001683

    Article  PubMed  CAS  Google Scholar 

  • Balla S, Nusair MB, Alpert MA (2013) Risk factors for atherosclerosis in patients with chronic kidney disease: recognition and management. Curr Opin Pharmacol 13(2):192–199

    Article  CAS  PubMed  Google Scholar 

  • Brunnemann KD, Hecht SS, Hoffmann D (1982) N-nitrosamines: environmental occurrence, in vivo formation and metabolism. J Toxicol Clin Toxicol 19(6–7):661–688

    Article  CAS  PubMed  Google Scholar 

  • Buensuceso CS, Obergfell A, Soriani A, Eto K, Kiosses WB, Arias-Salgado EG, Kawakami T, Shattil SJ (2005) Regulation of outside-in signaling in platelets by integrin-associated protein kinase C beta. J Biol Chem 280(1):644–653

    Article  CAS  PubMed  Google Scholar 

  • Chen TK, Knicely DH, Grams ME (2019) Chronic kidney disease diagnosis and management: a review. JAMA 322(13):1294–1304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A, European Uremic Toxin Work, G. (2012) Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol 23(7):1258–1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fennema D, Phillips IR, Shephard EA (2016) Trimethylamine and trimethylamine N-Oxide, a flavin-containing monooxygenase 3 (FMO3)-mediated host-microbiome metabolic axis implicated in health and disease. Drug Metab Dispos 44(11):1839–1850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freedman JE, Loscalzo J (2002) Platelet-monocyte aggregates: bridging thrombosis and inflammation. Circulation 105(18):2130–2132

    Article  PubMed  Google Scholar 

  • Harper MT, Poole AW (2010) Diverse functions of protein kinase C isoforms in platelet activation and thrombus formation. J Thromb Haemost 8(3):454–462

    Article  CAS  PubMed  Google Scholar 

  • Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, Hobbs FD (2016) Global prevalence of chronic kidney disease - a systematic review and meta-analysis. PLoS One 11(7):e0158765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hofmann F (2018) PKC and calcium channel trafficking. Channels (Austin) 12(1):15–16

    Article  Google Scholar 

  • Hsu CN, Chang-Chien GP, Lin S, Hou CY, Lu PC, Tain YL (2020) Association of trimethylamine, trimethylamine N-oxide, and dimethylamine with cardiovascular risk in children with chronic kidney disease. J Clin Med 9(2):336

    Article  CAS  PubMed Central  Google Scholar 

  • Jung SH, Han JH, Park HS, Lee JJ, Yang SY, Kim YH, Heo KS, Myung CS (2017) Inhibition of collagen-induced platelet aggregation by the Secobutanolide Secolincomolide A from Lindera obtusiloba Blume. Front Pharmacol 8:560

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA et al (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19(5):576–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konopatskaya O, Gilio K, Harper MT, Zhao Y, Cosemans JM, Karim ZA, Whiteheart SW, Molkentin JD, Verkade P, Watson SP, Heemskerk JW, Poole AW (2009) PKCalpha regulates platelet granule secretion and thrombus formation in mice. J Clin Invest 119(2):399–407

    CAS  PubMed  PubMed Central  Google Scholar 

  • Landray MJ, Wheeler DC, Lip GY, Newman DJ, Blann AD, McGlynn FJ, Ball S, Townend JN, Baigent C (2004) Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study. Am J Kidney Dis 43(2):244–253

    Article  CAS  PubMed  Google Scholar 

  • Lin JK, Chang HW, Lin-Shiau SY (1984) Abundance of dimethylamine in seafoods: possible implications in the incidence of human cancer. Nutr Cancer 6(3):148–159

    Article  CAS  PubMed  Google Scholar 

  • Liverani E, Mondrinos MJ, Sun S, Kunapuli SP, Kilpatrick LE (2018) Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. PLoS One 13(4):e0195379

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Meyer TW, Hostetter TH (2014) Approaches to uremia. J Am Soc Nephrol 25(10):2151–2158

    Article  PubMed  PubMed Central  Google Scholar 

  • Mitchell SC, Zhang AQ, Noblet JM, Gillespie S, Jones N, Smith RL (1997) Metabolic disposition of [14C]-trimethylamine N-oxide in rat: variation with dose and route of administration. Xenobiotica 27(11):1187–1197

    Article  CAS  PubMed  Google Scholar 

  • Mobarrez F, Antovic J, Egberg N, Hansson M, Jorneskog G, Hultenby K, Wallen H (2010) A multicolor flow cytometric assay for measurement of platelet-derived microparticles. Thromb Res 125(3):e110-116

    Article  CAS  PubMed  Google Scholar 

  • Ogawa T, Kimoto M, Watanabe H, Sasaoka K (1987) Metabolism of NG, NG-and NG, N’G-dimethylarginine in rats. Arch Biochem Biophys 252(2):526–537

    Article  CAS  PubMed  Google Scholar 

  • Pula G, Schuh K, Nakayama K, Nakayama KI, Walter U, Poole AW (2006) PKCdelta regulates collagen-induced platelet aggregation through inhibition of VASP-mediated filopodia formation. Blood 108(13):4035–4044

    Article  CAS  PubMed  Google Scholar 

  • Scanlan RA (1983) Formation and occurrence of nitrosamines in food. Cancer Res 43(5 Suppl):2435s–2440s

    CAS  PubMed  Google Scholar 

  • Shattil SJ, Cunningham M, Hoxie JA (1987) Detection of activated platelets in whole blood using activation-dependent monoclonal antibodies and flow cytometry. Blood 70(1):307–315

    Article  CAS  PubMed  Google Scholar 

  • Simenhoff ML, Saukkonen JJ, Burke JF, Schaedler RW, Vogel WH, Bovee K, Lasker N (1978) Importance of aliphatic amines in uremia. Kidney Int Suppl (8):S16–S19

  • Soltoff SP (2007) Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta. Trends Pharmacol Sci 28(9):453–458

    Article  CAS  PubMed  Google Scholar 

  • Strom AR, Olafsen JA, Larsen H (1979) Trimethylamine oxide: a terminal electron acceptor in anaerobic respiration of bacteria. J Gen Microbiol 112(2):315–320

    Article  CAS  PubMed  Google Scholar 

  • Tang WH (2016) Trimethylamine N-Oxide as a novel therapeutic target in CKD. J Am Soc Nephrol 27(1):8–10

    Article  PubMed  CAS  Google Scholar 

  • Teerlink T, Hennekes MW, Mulder C, Brulez HF (1997) Determination of dimethylamine in biological samples by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 691(2):269–276

    Article  CAS  PubMed  Google Scholar 

  • Tomlinson JAP, Wheeler DC (2017) The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease. Kidney Int 92(4):809–815

    Article  CAS  PubMed  Google Scholar 

  • Tsikas D (2020) Urinary Dimethylamine (DMA) and its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and beyond. J Clin Med 9(6):1843

    Article  CAS  PubMed Central  Google Scholar 

  • Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K, Ohno S (1996) Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf. J Biol Chem 271(38):23512–23519

    Article  CAS  PubMed  Google Scholar 

  • Vickers JD (1999) Binding of polymerizing fibrin to integrin alpha(IIb)beta(3) on chymotrypsin-treated rabbit platelets decreases phosphatidylinositol 4,5-bisphosphate and increases cytoskeletal actin. Platelets 10(4):228–237

    Article  CAS  PubMed  Google Scholar 

  • Windahl K, Faxen Irving G, Almquist T, Liden MK, van de Luijtgaarden M, Chesnaye NC, Voskamp P, Stenvinkel P, Klinger M, Szymczak M, Torino C, Postorini M et al (2018) Prevalence and risk of protein-energy wasting assessed by subjective global assessment in older adults with advanced chronic kidney disease: results from the EQUAL study. J Ren Nutr 28(3):165–174

    Article  PubMed  Google Scholar 

  • Wouters OJ, O’Donoghue DJ, Ritchie J, Kanavos PG, Narva AS (2015) Early chronic kidney disease: diagnosis, management and models of care. Nat Rev Nephrol 11(8):491–502

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu Q, Zhao Y, Zhang X, Yang X (2019) A faster and simpler UPLC-MS/MS method for the simultaneous determination of trimethylamine N-oxide, trimethylamine and dimethylamine in different types of biological samples. Food Funct 10(10):6484–6491

    Article  CAS  PubMed  Google Scholar 

  • Yacoub D, Theoret JF, Villeneuve L, Abou-Saleh H, Mourad W, Allen BG, Merhi Y (2006) Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 activation, and thromboxane A2 release. J Biol Chem 281(40):30024–30035

    Article  CAS  PubMed  Google Scholar 

  • Yang K, Wang C, Nie L, Zhao X, Gu J, Guan X, Wang S, Xiao T, Xu X, He T, Xia X, Wang J et al (2015) Klotho protects against indoxyl sulphate-induced myocardial hypertrophy. J Am Soc Nephrol 26(10):2434–2446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu J, Zhang TT, Gao X, Xue CH, Xu J, Wang YM (2017) Fish oil affects the metabolic process of trimethylamine N-oxide precursor through trimethylamine production and flavin-containing monooxygenase activity in male C57BL/6 mice. RSC Adv (7):56655–56661

  • Zaid Y, Senhaji N, Darif Y, Kojok K, Oudghiri M, Naya A (2016) Distinctive roles of PKC delta isozyme in platelet function. Curr Res Transl Med 64(3):135–139

    Article  CAS  PubMed  Google Scholar 

  • Zeisel SH, DaCosta KA, Fox JG (1985) Endogenous formation of dimethylamine. Biochem J 232(2):403–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang AQ, Mitchell SC, Barrett T, Ayesh R, Smith RL (1994) Fate of dimethylamine in man. Xenobiotica 24(4):379–387

    Article  CAS  PubMed  Google Scholar 

  • Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM et al (2016) Gut Microbial Metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165(1):111–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hemodialysis, the Second Hospital of Hebei Medical University, No.215 Heping Western Road, Shijiazhuang, 053000, Hebei, China

    Yongning Gao, Jingjing Hou & Lihua Wang

  2. Department of Hematology, the Second Hospital of Hebei Medical University, No.215 Heping Western Road, Shijiazhuang, 053000, Hebei, China

    Jingyu Zhang

  3. Department of Emergency, the Second Hospital of Hebei Medical University, No.215 Heping Western Road, Shijiazhuang, 053000, Hebei, China

    Hui Chen

  4. Department of Gynaecology, the Second Hospital of Hebei Medical University, No.215 Heping Western Road, Shijiazhuang, 053000, Hebei, China

    Zhu Wang

Authors
  1. Yongning Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingyu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingjing Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lihua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jingyu Zhang.

Ethics declarations

Ethical approval

All of the experimental procedures were approved by the Animal Care Committee of the Second Hospital of Hebei Medical University.

Informed consent

Not applicable.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 439 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, Y., Zhang, J., Chen, H. et al. Dimethylamine enhances platelet hyperactivity in chronic kidney disease model. J Bioenerg Biomembr 53, 585–595 (2021). https://doi.org/10.1007/s10863-021-09913-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-021-09913-4

Keywords

Search

Navigation