Skip to main content
SpringerLink
Log in

Synthesis and Function of 20-Hydroxyeicosatetraenoic Acid in the Kidney

  • Chapter
Advances in Prostaglandin and Leukotriene Research

Part of the book series: Medical Science Symposia Series ((MSSS,volume 16))

  • 86 Accesses

Abstract

20-hydroxyeicosatetraenoic acid (20-HETE), the ω-hydroxylation product of arachidonic acid (AA), is the principal metabolite formed in tubular and vascular structures of the rat renal cortex and outer medulla. 20-HETE has potent biological activities and has been shown to contribute to the regulation of renal function and to the control of arterial pressure. In the renal tubules it inhibits sodium reabsorption, while in the renal microcirculation it is a vasoconstrictor and a regulator of the myogenic response. The ω-hydroxylation of fatty acids, including AA, is catalyzed by enzymes of the cytochrome P450 (CYP) 4A family. In the rat, four isoforms have been identified: CYP4A1, 4A2, 4A3, and 4A8. Our studies indicated that despite the high homology, these isoforms display distinct catalytic properties including differences in kinetic parameters, product profile and inhibitor sensitivity. While the constitutive level of expression of CYP4A1 is low, its recombinant form is the low Km AA-ω-hydroxylase and thus, by far, the most efficient 20-HETE synthesizing enzyme. Whereas CYP4A1 is solely an AA whydroxylase, CYP4A2 and CYP4A3 also catalyze AA 11,12-epoxidation. Systemic administration of CYP4A antisense oligodeoxynucleotides revealed that CYP4A1 contributes significantly to the renal tubular and vascular production of 20-HETE. Furthermore, these isoforms demonstrate unique intrarenal localization. Using molecular and pharmacological probes we demonstrated a unique CYP4A isoform-specific localization within the renal microvasculature. Transfection of CYP4A1 cDNA to renal microvessels resulted in enhanced 20-HETE synthesis and increased reactivity to phenylephrine. Thus, 20-HETE of vascular origin serves as a stimulatory regulator of vascular responses to constrictor agonists.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Gibson GG. Comparative aspects of the mammalian cytochrome P450 IV gene family. Xenobiotica 1989; 19: 1123–48.

    Article  PubMed  CAS  Google Scholar 

  2. Kimura S, Hanioka N, Matsunaga E, Gonzalez FJ. The rat clofibrate-inducible CYP4A gene subfamily I. Complete intron and exon sequence of the CYP4A1 and CYP4A2 genes, unique exon organization, and identification of a conserved 19-bp upstream element. DNA 1989; 8: 503–16.

    Article  PubMed  CAS  Google Scholar 

  3. Kimura S, Hardwick JP, Kozak CA, Gonzalez FJ. The rat clofibrate-inducible CYP4A gene subfamily. II. cDNA sequence of IVA3, mapping of the Cyp4a locus to mouse chromosome 4, and coordinate and tissue-specific regulation of the CYP4A genes. DNA 1989; 8: 517–25.

    Article  PubMed  CAS  Google Scholar 

  4. Stromstedt M, Hayashi SI, Zaphiropoulos PG, Gustafsson JA. Cloning and characterization of a novel member of the cytochrome P450 subfamily IVA in rat prostate. DNA 1990; 9: 567–77.

    Article  Google Scholar 

  5. Hardwick W. CYP 4A subfamily: functional analysis by immunocytochemistry and in situ hybridization. Meth Enzymol 1991; 206: 273–83.

    Article  PubMed  CAS  Google Scholar 

  6. Iwai N, Inagami T. Isolation of preferentially expressed genes in the kidneys of hypertensive rats. Hypertension 1991; 17: 161–69.

    Article  PubMed  CAS  Google Scholar 

  7. Imig JD, Zou A-P, Stec DE, Harder DR, Falck JR, Roman RJ. Formation and actions of 20-hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol 1996; 270: R217 - R227.

    PubMed  CAS  Google Scholar 

  8. Imaoka S, Yamazoe Y, Kato R, Funae Y. Hormonal regulation of rat cytochrome P450s by androgen and pituitary. Arch Biochem Biophys 1992; 299: 179–84.

    Article  PubMed  CAS  Google Scholar 

  9. Sundseth SS, Waxman DJ. Sex-dependent expression and clofibrate inducibility of cytochrome P450 4A fatty acid w-hydroxylases. J Biol Chem 1993; 267: 3915–21.

    Google Scholar 

  10. Stromstedt M, Warner M, Gustafsson JA. Cytochrome P450s of the 4A subfamily in the brain. J Neurochem 1994; 63: 671–76.

    Article  PubMed  CAS  Google Scholar 

  11. Ito O, Alonso-galicia M, Hopp KA, Roman RJ. Localization of cytochrome P-450 4A isoforms along the rat nephron. Am J Physiol 1998; 274: F395 - F404.

    PubMed  CAS  Google Scholar 

  12. Wang M-H, Stec DE, Balazy M, et al. Cloning, sequencing and cDNA-directed expression of the rat renal CYP4A2: arachidonic acid w-hydroxylation and 11,12epoxidation by CYP4A2 protein. Arch Biochem Biophys 1996; 336: 240–50.

    Article  PubMed  CAS  Google Scholar 

  13. Nguyen X, Wang MH, Reddy KM, Falck JR, Schwartzman ML. Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors. Am J Physiol 1999; 276: R1691 - R1700.

    PubMed  CAS  Google Scholar 

  14. Laniado Schwartzman M, Da Silva J-L, Lin F, Nishimura M, Abraham NG. Cytochrome P450 4A expression and arachidonic acid w-hydroxylation in the kidney of the spontaneously hypertensive rat. Nephron 1996; 73: 652–63.

    Article  Google Scholar 

  15. Kroetz DL, Huse LM, Thuresson A, Grillo MP. Developmentally regulated expression of the CYP4A genes in the spontaneously hypertensive rat kidney. Mol Pharmaco11997; 52: 362–72.

    Google Scholar 

  16. Imaoka S, Funae Y. Hepatic and renal cytochrome P450s in spontaneously hypertensive rats. Biochim Biophys Acta 1991; 1074: 209–13.

    Article  PubMed  CAS  Google Scholar 

  17. Ornata K, Abraham NG, Escalante B, Laniado Schwartzman M. Age-related changes in renal cytochrome P450 arachidonic acid metabolism in spontaneously hypertensive rats. Am J Physiol 1992; 262: F8 - F16.

    Google Scholar 

  18. Sacerdoti D, Escalante B, Abraham NG, McGiff JC, Levere RD, Schwartzman ML. Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats. Science 1989; 243: 388–90.

    Article  PubMed  CAS  Google Scholar 

  19. Levere RD, Martesak P, Escalante B, Schwartzman ML, Abraham NG. Effect of heure arginate administration on blood pressure in spontaneously hypertensive rats. J Clin Invest 1990; 86: 213–19.

    Article  PubMed  CAS  Google Scholar 

  20. Su P, Kaushal KM, Kroetz DL. Inhibition of renal arachidonic acid omega-hydroxylase activity with ABT reduces blood pressure in the SHR. Am J Physiol 1998;275:R426–R43 8.

    Google Scholar 

  21. Stec DE, Trolleit MR, Krieger JE, Jacob HJ, Roman RJ. Cytochrome P4504A activity and salt sensitivity in spontaneously hypertensive rats. Hypertension 1996; 27: 1329–36.

    Article  PubMed  CAS  Google Scholar 

  22. Stec DE, Deng AY, Rapp JP, Roman RJ. Cytochrome P4504A genotype cosegregates with hypertension in Dahl S rats. Hypertension 1996; 27: 564–68.

    Article  PubMed  CAS  Google Scholar 

  23. Wang M-H, Guan H, Nguyen X, Zand B, Nasjletti A, Laniado-Schwartzman M. Contribution of cytochrome P450 4A1 and 4A2 to vascular 20-hydroxyeicosatetraenoic acid synthesis in the rat kidney. Am J Physiol 1998; 276: F246 - F253.

    Google Scholar 

  24. Roman RJ, Ma Y-H, Frohlich B, Markham B. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension 1993; 21: 985–88.

    Article  PubMed  CAS  Google Scholar 

  25. Omata K, Abraham NG, Laniado Schwartzman M. Arachidonic acid w/w-1 hydroxylase along the nephron of the spontaneously hypertensive rat. Am J Physiol 1992; 262: F59299.

    Google Scholar 

  26. Laniado Schwartzman M, Abraham NG. The renal cytochrome P450 arachidonic acid system. Pediat Nephrol 1992; 6: 490–98.

    Article  Google Scholar 

  27. Lu M, Zhu Y, Balazy M, Reddy KM, Falck JR, Wang W-H. Effect of angiotensin II on the apical K+ channel in the thick ascending limb of the rat kidney. J Gen Physiol 1996; 108: 537–47.

    Article  PubMed  CAS  Google Scholar 

  28. Ito O, Roman RJ. Regulation of P-450 4A activity in the glomerulus of the rat. Am J Physiol 1999; 76: R1749 - R1757.

    Google Scholar 

  29. Laniado Schwartzman M, Ornata K, Lin F, Bhatt RK, Abraham NG. Detection of 20hydroxyeicosatetraenoic acid in rat urine. Biochem Biophys Res Commun 1991; 180: 44549.

    Google Scholar 

  30. Prakash C, Zang JY, Falck JR, Chauhan K, Blair IA. 20-hydroxyeicosatetraenoic acid is excreted as a glucuronide conjugate in human urine. Biochem Biophys Res Commun 1992; 185: 728–33.

    Article  PubMed  CAS  Google Scholar 

  31. Escalante B, Sessa WC, Falck JR, Yadagiri P, Schwartzman ML. Vasoactivity of 20hydroxyeicosatetraenoic acid is dependent on metabolism by cyclooxygenase. J Pharmacol Exp Ther 1988; 248: 229–32.

    Google Scholar 

  32. Laniado Schwartzman M, Falck JR, Yadagiri P, Escalante B. Metabolism of 20hydroxyeicosatetraenoic acid by cyclooxygenase: formation and identification of novel endothelium-dependent vasoconstrictor metabolites. J Biol Chem 1989; 264: 1165–62.

    Google Scholar 

  33. Escalante B, Omata K, Sessa W, lee S-G, Falck JR, Laniado-Schwartzman M. 20-hydroxyeicosatetraenoic acid is an endothelium-dependent vasoconstrictor in rabbit arteries. Eur J Pharmacol 1993; 235: 1–7.

    Article  PubMed  CAS  Google Scholar 

  34. Ma Y-H, Gebremedhin D, Schwartzman ML, et al. 20-hydroxyeicosatetraenoic acid is an endogenous vasoconstrictor of canine renal arcuate arteries. Circ Res 1993; 72: 126–36.

    Article  PubMed  CAS  Google Scholar 

  35. Imig JD, Falck JR, Roman RJ. 20-hydroxyeicosatetraenoic acid (20-HETE) is a potent endogenous vasoconstrictor of renal arterioles. FASEB J 1993; 7: A888.

    Google Scholar 

  36. Escalante B, Erlij D, Falck JR, McGiffJC. Cytochrome P450 arachidonate metabolites affect ion fluxes in rabbit medullary thick ascending limb. Am J Physiol 1994; 266: C1775 - C1782.

    PubMed  CAS  Google Scholar 

  37. Imig JD, Zou A-P, Ortiz-de-Montellano PR, Sui Z, Roman RJ. Cytochrome P450 inhibitors alter afferent arteriolar responses to elevations in pressure. Am J Physiol 1994; 266: H1879 - H1885.

    PubMed  CAS  Google Scholar 

  38. Zou A-P, Imig JD, Kaldunski M, Ortiz de Montellano PR, Sui Z, Roman RJ. Inhibition of renal vascular 20-HETE production impairs autoregulation of renal blood flow. Am J Physiol 1994; 266: F275 - F282.

    PubMed  CAS  Google Scholar 

  39. Zou A-P, Imig JD, Ortiz de Montellano PR, Sui Z, Falck JR, Roman RJ. Effect of P450 w-hydroxylase metabolites of arachidonic acid on tubuloglomerular feedback. Am J Physiol 1994; 266: F934 - F941.

    PubMed  CAS  Google Scholar 

  40. lterman MA, Chaurasia CS, Lu P, Hardwick JP, Hanzlik RP. Fatty acid discrimination and w-hydroxylation by cytochrome P4504A1 and cytochromeP4504A1/NADPH-P450 reductase fusion protein. Arch Biochem Biophys 1995; 320: 289–96.

    Article  Google Scholar 

  41. Zou A-P, Drummond HA, Roman RJ. Role of 20-HETE in elevating loop chloride reabsorption in Dahl SS/Jr rats. Hypertension 1996; 27: 631–5.

    Article  PubMed  CAS  Google Scholar 

  42. Gebremedhin D, Ma Y-H, Imig JD, Harder DR, Roman RJ. Role of cytochrome P450 in elevating renal vascular tone in spontaneously hypertensive rats. J Vasc Res 1993; 30: 5360.

    Google Scholar 

  43. Zou A-P, Fleming JT, Falck JR, et al. 20-HETE is an endogenous inhibitor of the large-conductance Cat+-activated IC channel in renal arterioles. Am J Physiol 1996; 270: R228 - R237.

    PubMed  CAS  Google Scholar 

  44. Lin F, Rios A, Falck JR, Belosludtsev Y, Laniado Schwartzman M. 20-hydroxyeicosatetraenoic acid is formed in response to EGF and is a mitogen in rat proximal tubule. Am J Physiol 1995; 269: F806 - F816.

    PubMed  CAS  Google Scholar 

  45. Wang W, Lu M. Effect of arachidonic acid on activity of the apical K+ channel in the thick ascending limb of the rat kidney. J Gen Physiol 1995; 106: 727–43.

    Article  PubMed  CAS  Google Scholar 

  46. Nowicki S, Chen SL, Aizman O, et al. 20-Hydroxyeicosa-tetraenoic acid (20 RETE) activates protein kinase C. Role in regulation of rat renal Na+,K+-ATPase. J Clin Invest 1997; 99: 1224–30.

    Article  PubMed  CAS  Google Scholar 

  47. Lange A, Gebremedhin D, Narayanan J, Harder D. 20-Hydroxyeicosatetraenoic acid-induced vasoconstriction and inhibition of potassium current in cerebral vascular smooth muscle is dependent on activation of protein kinase C. J Biol Chem 1997; 272: 27345–52.

    Article  PubMed  CAS  Google Scholar 

  48. Muthalif MM, Benter IF, Karzoun N, et al. 20-Hydroxyeicosatetraenoic acid mediates calcium/calmodulin-dependent protein kinase II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. Proc Natl Acad Sci USA 1998; 95: 12701–6.

    Article  PubMed  CAS  Google Scholar 

  49. Sun CW, Falck JR, Harder DR, Roman RJ. Role of tyrosine kinase and PKC in the vasoconstrictor response to 20- RETE in renal arterioles. Hypertension 1999; 33: 414–18.

    Article  PubMed  CAS  Google Scholar 

  50. Alonso-Galicia M, Falck JR, Reddy KM, Roman RJ. 20-BETE agonists and antagonists in the renal circulation. Am J Physiol 1999; 277: F790 - F796.

    PubMed  CAS  Google Scholar 

  51. Carroll MA, Balazy M, Huang DD, Rybalova S, Falck JR, McGiffJC. Cytochrome P450-derived renal HETEs: storage and release. Kidney Int 1997; 51: 1696–702.

    Article  PubMed  CAS  Google Scholar 

  52. Oyekan AO, McGiffJC. Cytochrome P-450-derived eicosanoids participate in the renal functional effects of ET-1 in the anesthetized rat. Am J Physiol 1998; 274: R52 - R61.

    PubMed  CAS  Google Scholar 

  53. Pedrosa CM, Dubay GR, Falck JR, Mandel LJ. Parathyroid hormone inhibits Na+-K+ATPase through a cytochrome P450 pathway. Am J Physiol 1994; 266: F497 - F505.

    Google Scholar 

  54. Amlal H, LeGoff C, Vernimmen C, Soleimani M, Paillard M, Bichara M. ANG II controls Na(+)-1C(NH°+)-2C1- cotransport via 20-RETE and PKC in medullary thick ascending limb. Am J Physiol 1998; 274: C1047 - C1056.

    PubMed  CAS  Google Scholar 

  55. Grider JS, Falcone JC, Kilpatrick EL, Ott CE, Jackson BA. P450 arachidonate metabolites mediate bradykinin-dependent inhibition of NaC1 transport in the rat thick ascending limb. Can J Physiol Pharmacol 1997; 75: 91–96.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Michal Laniado Schwartzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jackleen Marji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mong-Heng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institute, S-171 77, Stockholm, Sweden

    Bengt Samuelsson

  2. Department of Pharmacological Sciences, University of Milan, Milan, Italy

    R. Paoletti , Giancarlo C. Folco  & S. Nicosia ,  & 

  3. Center for Cardiopulmonary Pharmacology, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy

    Giancarlo C. Folco

  4. Karolinska Hospital, Stockholm, Sweden

    E. Granström

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Schwartzman, M.L., Marji, J., Jiang, M., Wang, MH. (2001). Synthesis and Function of 20-Hydroxyeicosatetraenoic Acid in the Kidney. In: Samuelsson, B., Paoletti, R., Folco, G.C., Granström, E., Nicosia, S. (eds) Advances in Prostaglandin and Leukotriene Research. Medical Science Symposia Series, vol 16. Springer, Dordrecht. https://doi.org/10.1007/978-94-015-9721-0_17

Download citation

  • DOI: https://doi.org/10.1007/978-94-015-9721-0_17

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-90-481-5881-2

  • Online ISBN: 978-94-015-9721-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation