Skip to main content
SpringerLink
Log in

The effect of three angiotensin-converting enzyme inhibitors on kynurenic acid production in rat kidney in vitro

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

The renin-angiotensin system (RAS) is commonly known to regulate blood pressure, water and electrolyte homeostasis, however it also exerts paracrine and autocrine actions on the kidney. Angiotensin-converting enzyme inhibitors (ACE-Is), alongside their hypotensive properties, have been shown to decrease kidney function decline in animal models of nephropathy.

Glutamate (GLU) is the main stimulatory neurotransmitter in the central nervous system, however its importance in the periphery should also be considered. Activation of renal GLU receptors has been linked to normal kidney function and also renal injury. The wide spectrum GLU receptor antagonist kynurenic acid (KYNA) possesses neuroprotective and central hypotensive effects, however its actions outside the brain are less well recognized. KYNA is a tryptophan metabolite synthesized from kynurenine by kynurenine aminotransferases (KATs). The purpose of this study was to examine the influence of three ACE-Is: lisinopril, perindopril and ramipril on KYNA production and KATs activity in rat kidney in vitro.

Methods

The effect of ACE-Is on KYNA production and KATs activity was examined in rat kidney homogenates. KYNA was detected by high-performance liquid chromatography (HPLC) and quantified fluorometrically.

Results

All examined ACE-Is: lisinopril, perindopril and ramipril decreased KYNA production in rat kidney in vitro. KAT I activity was decreased by lisinopril and ramipril whereas the activity of KAT II was lowered by ramipril.

Conclusion

Our study shows that ACE-Is can decrease KYNA production in rat kidney in vitro. Further studies are required to determine the clinical importance of the inhibitory action of ACE-Is on KYNA synthesis in the kidney.

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

Similar content being viewed by others

References

  1. Nasri H, Rafieian-Kopaei M. On the occasion of world kidney day 2016; work together to better protect the kidney. J Nephropathol 2016;5(1):15–8.

    Article  PubMed  Google Scholar 

  2. Stanifer JW, Muiru A, Jafar TH, Patel UD. Chronic kidney disease in low- and middle-income countries. Nephrol Dial Transplant 2016;31(6):868–74.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mizuiri S, Ohashi Y. ACE and ACE2 in kidney disease. World J Nephrol 2015;4 (1):74–82.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Viazzi F, Bonino B, Cappadona F, Pontremoli R. Renin-angiotensin-aldosterone system blockade in chronic kidney disease: current strategies and a look ahead. Intern Emerg Med 2016;11(5):627–35.

    Article  PubMed  Google Scholar 

  5. Portero-Otín M, Pamplona R, Boada J, Jové M, Gonzalo H, Buleon M, et al. Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats. Biochem Biophys Res Commun 2008;368(3):528–35.

    Article  PubMed  CAS  Google Scholar 

  6. Schießl IM, Kattler V, Castrop H. In vivo visualization of the antialbuminuric effects of the angiotensin-converting enzyme inhibitor enalapril. J Pharmacol Exp Ther 2015;353(2):299–306.

    Article  PubMed  CAS  Google Scholar 

  7. Izzo Jr. JL, Weir MR. Angiotensin-converting enzyme inhibitors. J Clin Hypertens (Greenwich). 2011;13(9):667–75.

    Article  CAS  Google Scholar 

  8. Dryer SE. Glutamate receptors in the kidney. Nephrol Dial Transplant 2015;30 (10):1630–8.

    Article  CAS  PubMed  Google Scholar 

  9. Szaroma W, Dziubek K, Kapusta E. Effect of N-methyl-D-aspartic acid on activity of superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione level in selected organs of the mouse. Acta Physiol Hung 2014;101(3):377–87.

    Article  CAS  PubMed  Google Scholar 

  10. Pundir M, Arora S, Kaur T, Singh R, Singh AP. Effect of modulating the allosteric sites of N-methyl-D-aspartate receptors in ischemia-reperfusion induced acute kidney injury. J Surg Res 2013;183(2):668–77.

    Article  CAS  PubMed  Google Scholar 

  11. Du J, Li XH, Li YJ. Glutamate in peripheral organs: biology and pharmacology. Eur J Pharmacol 2016;784:42–8.

    Article  CAS  PubMed  Google Scholar 

  12. Gill SS, Pulido OM. Glutamate receptors in peripheral tissues: current knowledge, future research, and implications for toxicology. Toxicol Pathol 2001;29(2):208–23.

    Article  CAS  PubMed  Google Scholar 

  13. Leung JC, Marphis T, Craver RD, Silverstein DM. Altered NMDA receptor expression in renal toxicity: protection with a receptor antagonist. Kidney Int 2004;66(1):167–76.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang C, Yi F, Xia M, Boini KM, Zhu Q, Laperle LA, et al. NMDA receptor-mediated activation of NADPH oxidase and glomerulosclerosis in hyperhomocysteinemic rats. Antioxid Redox Signal 2010;13(7):975–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, et al. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A 1988;85(17):6547–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Doi K, Tsumoto T, Matsunaga T. Actions of excitatory amino acid antagonists on synaptic inputs to the rat medial vestibular nucleus: an electrophysiological study in vitro. Exp Brain Res 1990;82(2):254–62.

    Article  CAS  PubMed  Google Scholar 

  17. Németh H, Toldi J, Vécsei L. Role of kynurenines in the central and peripheral nervous systems. Curr Neurovasc Res 2005;2(3):249–60.

    Article  PubMed  Google Scholar 

  18. Pawlak D, Tankiewicz A, Matys T, Buczko W. Peripheral distribution of kynurenine metabolites and activity of kynurenine pathway enzymes in renal failure. J Physiol Pharmacol 2003;54(2):175–89.

    CAS  PubMed  Google Scholar 

  19. Liebig J. Über kynurensäure. Justus Liebigs Ann Chem 1853;86(1):125–6.

    Article  Google Scholar 

  20. Zhao J, Chen H, Ni P, Xu B, Luo X, Zhan Y, et al. Simultaneous determination of urinary tryptophan, tryptophan-related metabolites and creatinine by high performance liquid chromatography with ultraviolet and fluorimetric detection. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879(26):2720–5.

    Article  CAS  PubMed  Google Scholar 

  21. Schwarcz R, Speciale C, French ED. Hippocampal kynurenines as etiological factors in seizure disorders. Pol J Pharmacol Pharm 1987;39(5):485–94.

    CAS  PubMed  Google Scholar 

  22. Németh H, Toldi J, Kynurenines Vécsei L. Parkinson’s disease and other neurodegenerative disorders: preclinical and clinical studies. J Neural Transm Suppl 2006;28(70):5–304.

    Google Scholar 

  23. Erhardt S, Olsson SK, Engberg G. Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs 2009;23 (2):91–101.

    Article  CAS  PubMed  Google Scholar 

  24. Ito S, Komatsu K, Tsukamoto K, Sved AF. Excitatory amino acids in the rostral ventrolateral medulla support blood pressure in spontaneously hypertensive rats. Hypertension 2000;35(1 Pt 2):413–7.

    Article  CAS  PubMed  Google Scholar 

  25. Araujo GC, Lopes OU, Campos RR. Importance of glycinergic and glutamatergic synapses within the rostral ventrolateral medulla for blood pressure regulation in conscious rats. Hypertension 1999;34(4 Pt 2):752–5.

    Article  CAS  PubMed  Google Scholar 

  26. Zakrocka I, Turski WA, Kocki T. Angiotensin-converting enzyme inhibitors modulate kynurenic acid production in rat brain cortex in vitro. Eur J Pharmacol 2016;789:308–12.

    Article  CAS  PubMed  Google Scholar 

  27. Sanmartín-Suárez C, Soto-Otero R, Sánchez-Sellero I, Méndez-Álvarez E. Antioxidant properties of dimethyl sulfoxide and its viability as a solvent in the evaluation of neuroprotective antioxidants. J Pharmacol Toxicol Methods 2011;63(2):209–15.

    Article  PubMed  CAS  Google Scholar 

  28. White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among ACE inhibitors. Pharmacotherapy 1998;18(3):588–99.

    CAS  PubMed  Google Scholar 

  29. Tsai HH, Lees KR, Howden CW, Reid JL. The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis. Br J Clin Pharmacol 1989;28(1):53–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Thomsen R, Rasmussen HB, Linnet K. INDICES Consortium: in vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors. Drug Metab Dispos 2014;42(1):126–33.

    Article  CAS  PubMed  Google Scholar 

  31. Meisel S, Shamiss A, Rosenthal T. Clinical pharmacokinetics of ramipril. Clin Pharmacokinet 1994;26(1):7–15.

    Article  CAS  PubMed  Google Scholar 

  32. Cushman DW, Wang FL, Fung WC, Grover GJ, Harvey CM, Scalese RJ, et al. Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE). Br J Clin Pharmacol 1989;28(Suppl. 2):115S–30S.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Grima M, Welsch C, Michel B, Barthelmebs M, Imbs JL. In vitro tissue potencies of converting enzyme inhibitors: prodrug activation by kidney esterase. Hypertension 1991;17(4):492–6.

    Article  CAS  PubMed  Google Scholar 

  34. Kaihara M, Price JM, Takahashi H. The conversion of kynurenic acid to quinaldic acid by humans and rats. J Biol Chem 1956;223(2):705–8.

    CAS  PubMed  Google Scholar 

  35. Turski WA, Schwarcz R. On the disposition of intrahippocampally injected kynurenic acid in the rat. Exp Brain Res 1988;71(3):563–7.

    Article  CAS  PubMed  Google Scholar 

  36. Bergamaschi C, Campos RR, Schor N, Lopes OU. Role of the rostral ventrolateral medulla in maintenance of blood pressure in rats with Goldblatt hypertension. Hypertension 1995;26(6 Pt 2):1117–20.

    Article  CAS  PubMed  Google Scholar 

  37. Deng A, Thomson SC. Renal NMDA receptors independently stimulate proximal reabsorption and glomerular filtration. Am J Physiol Renal Physiol 2009;296(5):F976–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Smothers CT, Woodward JJ. Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits. J Pharmacol Exp Ther 2007;322(2):739–48.

    Article  CAS  PubMed  Google Scholar 

  39. Sproul A, Steele SL, Thai TL, Yu S, Klein JD, Sands JM, et al. N-methyl-D-aspartate receptor subunit NR3a expression and function in principal cells of the collecting duct. Am J Physiol Renal Physiol 2011;301(1):F44–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Anderson M, Suh JM, Kim EY, Dryer SE. Functional NMDA receptors with atypical properties are expressed in podocytes. Am J Physiol Cell Physiol 2011;300(1):C22–32.

    Article  CAS  PubMed  Google Scholar 

  41. Roshanravan H, Kim EY, Dryer SE. NMDA receptors as potential therapeutic targets in diabetic nephropathy: increased renal NMDA receptor subunit expression in Akita mice and reduced nephropathy following sustained treatment with memantine or MK-801. Diabetes 2016;65(10):3139–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shen J, Wang R, He Z, Huang H, He X, Zhou J, et al. NMDA receptors participate in the progression of diabetic kidney disease by decreasing cdc42-GTP activation in podocytes. J Pathol 2016;240(2):149–60.

    Article  CAS  PubMed  Google Scholar 

  43. Arora S, Kaur T, Kaur A, Singh AP. Glycine aggravates ischemia reperfusion-induced acute kidney injury through N-Methyl-D-Aspartate receptor activation in rats. Mol Cell Biochem 2014;393(1–2):123–31.

    Article  CAS  PubMed  Google Scholar 

  44. Yang CC, Chien CT, Wu MH, Ma MC, Chen CF. NMDA receptor blocker ameliorates ischemia-reperfusion-induced renal dysfunction in rat kidneys. Am J Physiol Renal Physiol 2008;294(6):F1433–40.

    Article  CAS  PubMed  Google Scholar 

  45. Lin CS, Hung SF, Huang HS, Ma MC. Blockade of the N-Methyl-D-Aspartate glutamate receptor ameliorates lipopolysaccharide-Induced renal insufficiency. PLoS One 2015;10(7):e0132204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Parisi E, Bozic M, Ibarz M, Panizo S, Valcheva P, Coll B, et al. Sustained activation of renal N-methyl-D-aspartate receptors decreases vitamin D synthesis: a possible role for glutamate on the onset of secondary HPT. Am J Physiol Endocrinol Metab 2010;299(5):E825–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Foster AC, Kemp JA, Leeson PD, Grimwood S, Donald AE, Marshall GR, et al. Kynurenic acid analogues with improved affinity and selectivity for the glycine site on the N-methyl-D-aspartate receptor from rat brain. Mol Pharmacol 1992;41(5):914–22.

    CAS  PubMed  Google Scholar 

  48. Bądzyńska B, Zakrocka I, Sadowski J, Turski WA, Kompanowska-Jezierska E. Effects of systemic administration of kynurenic acid and glycine on renal haemodynamics and excretion in normotensive and spontaneously hypertensive rats. Eur J Pharmacol 2014;743:37–41.

    Article  PubMed  CAS  Google Scholar 

  49. Walczak K, Zurawska M, Kiś J, Starownik R, Zgrajka W, Bar K, et al. Kynurenic acid in human renal cell carcinoma: its antiproliferative and antimigrative action on Caki-2 cells. Amino Acids 2012;43(4):1663–70.

    Article  CAS  PubMed  Google Scholar 

  50. Che R, Yuan Y, Huang S, Zhang A. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 2014;306(4):F367–78.

    Article  CAS  PubMed  Google Scholar 

  51. Mutsaers HA, Wilmer MJ, Reijnders D, Jansen J, van den Broek PH, Forkink M, et al. Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration. Biochim Biophys Acta 2013;1832(1):142–50.

    Article  CAS  PubMed  Google Scholar 

  52. Giardino L, Armelloni S, Corbelli A, Mattinzoli D, Zennaro C, Guerrot D, et al. Podocyte glutamatergic signaling contributes to the function of the glomerular filtration barrier. J Am Soc Nephrol 2009;20(9):1929–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Leung JC, Ragland N, Marphis T, Silverstein DM. NMDA agonists and antagonists induce renal culture cell toxicity. Med Chem 2008;4(6):565–71.

    Article  CAS  PubMed  Google Scholar 

  54. Sekita-Krzak J, Visconti J, Wójtowicz Z, Zebrowska-Lupina I, Ossowska G, Klenk-Majewska B. Histological examination of the kidney after experimental administration of MK-801 and dexamethasone. Ann Univ Mariae Curie Sklodowska Med 2004;59(2):70–4.

    PubMed  Google Scholar 

  55. Kaczorek E, Szarek J, Mikiewicz M, Terech-Majewska E, Schulz P, Małaczewska J, et al. Effect of feed supplementation with kynurenic acid on the morphology of the liver, kidney and gills in rainbow trout (Oncorhynchus mykiss Walbaum, 1792), healthy and experimentally infected with Yersinia ruckeri. J Fish Dis 2016, doi:https://doi.org/10.1111/jfd.12567.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Lublin, Poland

    Izabela Zakrocka, Tomasz Kocki & Waldemar A. Turski

Authors
  1. Izabela Zakrocka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomasz Kocki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Waldemar A. Turski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Izabela Zakrocka.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zakrocka, I., Kocki, T. & Turski, W.A. The effect of three angiotensin-converting enzyme inhibitors on kynurenic acid production in rat kidney in vitro. Pharmacol. Rep 69, 536–541 (2017). https://doi.org/10.1016/j.pharep.2017.01.023

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2017.01.023

Keywords

Search

Navigation