LCN2

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Lipocalin 2
Protein LCN2 PDB 1dfv.png
PDB rendering based on 1dfv.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LCN2 ; 24p3; MSFI; NGAL
External IDs OMIM600181 MGI96757 HomoloGene4064 ChEMBL: 1741308 GeneCards: LCN2 Gene
RNA expression pattern
PBB GE LCN2 212531 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3934 16819
Ensembl ENSG00000148346 ENSMUSG00000026822
UniProt P80188 P11672
RefSeq (mRNA) NM_005564 NM_008491
RefSeq (protein) NP_005555 NP_032517
Location (UCSC) Chr 9:
130.91 – 130.92 Mb
Chr 2:
32.38 – 32.39 Mb
PubMed search [1] [2]

Lipocalin-2 (LCN2), also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), is a protein that in humans is encoded by the LCN2 gene.[1][2][3] NGAL is involved in innate immunity by sequestrating iron that in turn limits bacterial growth.[4] It is expressed in neutrophils and in low levels in the kidney, prostate, and epithelia of the respiratory and alimentary tracts.[3][5] NGAL is used as a biomarker of kidney injury.[6]

Function[edit]

The binding of NGAL to bacterial siderophores is important in the innate immune response to bacterial infection. Upon encountering invading bacteria the toll-like receptors on immune cells stimulate the synthesis and secretion of NGAL. Secreted NGAL then limits bacterial growth by sequestering iron-containing siderophores.[7][8] Lipocalin-2 also functions as a growth factor.[8]

Clinical significance[edit]

Immune response[edit]

Originally, NGAL was isolated from a supernatant of activated human neutrophils.[1] However, NGAL levels have also been shown to increase in patients with a low number of neutrophils due to leukemia, which indicates that increases in NGAL levels are not exclusively associated with neutrophils.[9]

Lack of LCN2 expression has been possibly linked to acne could be caused due to lack of gene expression, which possibly can be correct with Isotretinoin.[10][11]

Kidney function[edit]

In the case of acute kidney injury (AKI), NGAL is secreted in high levels into the blood and urine within 2 hours of injury.[12] Because NGAL is protease resistant and small, the protein is easily excreted and detected in the urine.[9] NGAL levels in patients with AKI have been associated with the severity of their prognosis and can be used as a biomarker for AKI[12] NGAL can also be used as an early diagnosis for procedures such as chronic kidney disease, contrast induced nephropathy, and kidney transplant.[13][14]

Kidney health is most frequently measured by serum creatinine. Serum creatinine is a marker of kidney function, whereas NGAL is a marker of kidney injury.[15] NGAL levels are a more precise and sensitive marker for diagnosing AKI than serum creatinine levels. Therefore, monitoring NGAL levels reduces delayed AKI diagnosis and treatment.[14] Using a more sensitive and specific marker allows for earlier diagnosis, correct responses to AKI, and reduced risk of morbidity and mortality.[16]

The NGAL level measured in an individual is proportional to the severity of the AKI.[16] Individuals positive for NGAL tend to have higher incidence of renal replacement therapy and have higher rates of in-hospital mortality, both in the presence and the absence of serum creatinine.[16] Therefore, an individual may have AKI without the presence of serum creatinine.

The ability to diagnose AKI before acute kidney failure is financially beneficial and favorable for preventative health measures. More than 10% of people in the United States will develop some kind of chronic kidney disease (CKD), with higher incidences for individuals that suffer from obesity, elevated cholesterol, and a family history of CKD. There is no point of return once there is a significant injury to the kidney; therefore, early diagnosis of kidney injury is important for preventing AKI. Using NGAL as a biomarker can lower hospital costs because less patients will reach a critical stage in kidney injury. Ultimately, diagnosis of AKI with NGAL can reduced the time a patient stays in a hospital. For example, the early diagnosis of AKI with NGAL as a biomarker can help a patient avoid kidney dialysis.

Other roles[edit]

NGAL can be used as a biomarker for percutaneous coronary interventions (PCI), cardiopulmonary bypass, and critically ill patients (heart failure, sepsis, multi-organ failure).[14] Acute kidney injury is common after these surgical procedures, especially if the individual suffers of high systolic blood pressure, renal dysfunction, or obesity.[17] The use of NGAL in these situations is more efficient than serum creatinine at diagnosing AKI.[14]

NGAL has also been shown to play a role in cancer. NFAT3 (NFATc4) inhibits breast carcinoma cell motility by blocking the expression of NGAL,[18] and NFAT1 modulates the axis to potentiate breast carcinoma motility by increasing the expression of NGAL.[19] Like NFAT1, NFAT5 modulates the expression of the NGAL and increases breast carcinoma migration.[20] NGAL has also been shown to be highly expressed in tumor cells.[21] Complexes such as NGAL-MMP-9 in the urine may have relevance as a biomarker for breast cancer.[22]

Other studies indicate NGAL as a player in bone turnover, it can enable osteoclast differentiation and inhibit osteoblast matrix deposition and maturation. Hence mice who overexpress NGAL are dwarfs.[23] This is due to the ability of osteoblasts to secrete LCN2 since first stages of development.

Laboratory measurement[edit]

Renal expression of NGAL increases in the kidneys after injury for a variety of reasons. The level of NGAL in the urine and plasma increases within 2 hours of kidney injury. It is possible to measure NGAL in serum or urine in the range of 25 to 5,000 ng/mL by current laboratory tests.[24] Low levels for NGAL have been considered to be 20 ng/mL, medium levels 200 ng/mL, and high levels 1200 ng/mL.[24]

A study on children with pediatric cardiopulmonary bypass operations showed that urinary NGAL concentrations above 50 ng/mL 2 hours after surgery is indicative of serum creatinine levels 50% over basal values. Normally, children tend to have almost undetectable levels of NGAL.[25] Therefore, studies that include children are considered to be “pure.” Adult patients presenting for cardiopulmonary bypass surgery are not considered to be “pure” in NGAL studies because adults often have other disorders such as inflammatory conditions, which can cause slight increases in NGAL.[citation needed]

AKI studies investigating the use of NGAL as a biomarker often compare serum creatinine and NGAL production. Unfortunately, serum creatinine production is variable; therefore, the comparison is not always reliable.[26] In addition, NGAL levels are relative to each person, and a study on specific numbers and their accurate predicted outcomes is yet to be done.

Although NGAL is generally a precise biomarker of AKI, there are limitations to the use of the biomarker. Studies have proven that NGAL is not only present when there is chance for AKI. There are many other ways to have elevated NGAL levels such as taking certain kinds of antibiotics and other endogenous substances. Creatinine, for example, can elevate NGAL levels and create a false positive for an AKI. There are also some medical conditions that may interfere with NGAL levels including Epstein-Barr Virus, Hepatitis A Virus, Herpes Simplex Virus, Myeloma, and Rubella Virus.[27]

Particle-enhanced turbidimetric immunoassay (PETIA)[edit]

PETIA is a turbidimetry test which runs on clinical chemistry analyzers with open channels. PETIA can be used to measure NGAL in the urine, heparin, and plasma in quantities of 25 to 5,000 ng/mL.[14] For an in vitro test, NGAL concentration can be determined with ELISA using urine, plasma, serum, tissue extracts or culture media.[14]

Point-of-Care NGAL test[edit]

The point-of-care NGAL test is an in-vitro test that uses a fluorescence immunoassay to measure NGAL levels in anticoagulated blood or plasma samples during triage. The test is initiated by adding a several drops of an EDTA anti-coagulated blood sample or plasma specimen to the test device, which filters out the blood cells from the plasma. The specimen reacts with fluorescent antibody conjugates and flows through the device to a discrete zone specific to the analyte. The amount of fluorescence expressed by the specimen is analyzed. The concentration of NGAL in the sample correlates directly to the amount of fluorescence.[28]

Immunoassay[edit]

An immunoassay is an in-vitro test that uses a chemiluminescent microparticle immunoassay (CMIA) to give a quantitative measurement of NGAL levels in a sample of urine. It utilizes microparticles coated with monoclonal antibodies, which set off a reaction that indicates how much NGAL is present in the sample.[26]

The test is initiated by diluting the sample with wash buffer and adding anti-NGAL coated paramagnetic microparticles. The NGAL in the urine binds to the microparticles and the reaction mixture is washed before adding an anti-NGAL acridinium-labeled conjugate. After another wash cycle, pre-trigger and trigger solutions are added to induce the chemiluminescent reaction. This reaction is measured in Relative Light Units (RLUs),which are proportional to the concentration of NGAL in the sample.[26]

History[edit]

In 2004, the US FDA announced that there is a need for increased product development involving biomarkers and surrogate markers. In particular, there has been intense research regarding the use of the NGAL biomarker.[14]

The first study conducted to determine if NGAL is effective as a biomarker was published in July 2011. The study found that the treatment with fenoldopam decreases urinary NGAL significantly after cardiac surgery. This suggests that fenoldopam has nephroprotective effects.[14] This study was important in defining NGALs role in AKI.

In the Philippines, the first guideline implementation of NGAL as a diagnostic biomarker occurred in 2010 for the detection of AKI in leptospirosis management.[14]

References[edit]

  1. ^ a b Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N (May 1993). "Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase". J. Biol. Chem. 268 (14): 10425–32. PMID 7683678. 
  2. ^ Chan P, Simon-Chazottes D, Mattei MG, Guenet JL, Salier JP (September 1994). "Comparative mapping of lipocalin genes in human and mouse: the four genes for complement C8 gamma chain, prostaglandin-D-synthase, oncogene-24p3, and progestagen-associated endometrial protein map to HSA9 and MMU2". Genomics 23 (1): 145–50. doi:10.1006/geno.1994.1470. PMID 7829063. 
  3. ^ a b Cowland JB, Borregaard N (October 1997). "Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans". Genomics 45 (1): 17–23. doi:10.1006/geno.1997.4896. PMID 9339356. 
  4. ^ Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J (November 2002). "An iron delivery pathway mediated by a lipocalin". Mol. Cell 10 (5): 1045–56. doi:10.1016/S1097-2765(02)00710-4. PMID 12453413. 
  5. ^ Friedl A, Stoesz SP, Buckley P, Gould MN (July 1999). "Neutrophil gelatinase-associated lipocalin in normal and neoplastic human tissues. Cell type-specific pattern of expression". Histochem. J. 31 (7): 433–41. doi:10.1023/A:1003708808934. PMID 10475571. 
  6. ^ Devarajan P (June 2010). "Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury". Nephrology (Carlton) 15 (4): 419–28. doi:10.1111/j.1440-1797.2010.01317.x. PMID 20609093. 
  7. ^ Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (December 2004). "Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron". Nature 432 (7019): 917–21. doi:10.1038/nature03104. PMID 15531878. 
  8. ^ a b Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J (February 2007). "Dual action of neutrophil gelatinase-associated lipocalin". J. Am. Soc. Nephrol. 18 (2): 407–13. doi:10.1681/ASN.2006080882. PMID 17229907. 
  9. ^ a b LO Uttenthal (2005). "NGAL: a marker molecule for the distressed kidney?". Clinical Laboratory International. 
  10. ^ Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM (April 2008). "Neutrophil gelatinase–associated lipocalin mediates 13-cis retinoic acid–induced apoptosis of human sebaceous gland cells". J. Clin. Invest. 118 (4): 1468–78. doi:10.1172/JCI33869. PMC 2262030. PMID 18317594. 
  11. ^ Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM (March–April 2009). "Early gene changes induced by isotretinoin in the skin provide clues to its mechanism of action". Dermato-Endocrinology 1 (2): 100–1. doi:10.4161/derm.1.2.8107. PMC 2835899. PMID 20224692. 
  12. ^ a b Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, Syed H, Ali S, Barasch J, Devarajan P (May 2008). "Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study". Clin J Am Soc Nephrol 3 (3): 665–73. doi:10.2215/CJN.04010907. PMC 2386703. PMID 18337554. 
  13. ^ Goldstein SL (2011). "Acute kidney injury biomarkers: renal angina and the need for a renal troponin I". BMC Med 9: 135. doi:10.1186/1741-7015-9-135. PMC 3287120. PMID 22189039. 
  14. ^ a b c d e f g h i ARCHITECT Urine NGAL. 2009. 
  15. ^ Han WK, Wagener G, Zhu Y, Wang S, Lee HT (May 2009). "Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery". Clin J Am Soc Nephrol 4 (5): 873–82. doi:10.2215/CJN.04810908. PMC 2676184. PMID 19406962. 
  16. ^ a b c Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, Krawczeski CD, Koyner JL, Murray P, Zappitelli M, Goldstein SL, Makris K, Ronco C, Martensson J, Martling CR, Venge P, Siew E, Ware LB, Ikizler TA, Mertens PR (April 2011). "The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies". J. Am. Coll. Cardiol. 57 (17): 1752–61. doi:10.1016/j.jacc.2010.11.051. PMID 21511111. 
  17. ^ Kim MY, Jang HR, Huh W, Kim YG, Kim DJ, Lee YT, Oh HY, Eun Lee J (2011). "Incidence, risk factors, and prediction of acute kidney injury after off-pump coronary artery bypass grafting". Ren Fail 33 (3): 316–22. doi:10.3109/0886022X.2011.560406. PMID 21401357. 
  18. ^ Fougère M, Gaudineau B, Barbier J, Guaddachi F, Feugeas JP, Auboeuf D, Jauliac S (April 2010). "NFAT3 transcription factor inhibits breast cancer cell motility by targeting the Lipocalin 2 gene". Oncogene 29 (15): 2292–301. doi:10.1038/onc.2009.499. PMID 20101218. 
  19. ^ Gaudineau B, Fougère M, Guaddachi F, Lemoine F, de la Grange P, Jauliac S (July 2012). "Lipocalin 2 (LCN2), the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion". J Cell Sci 125 (Pt 19): 4475–86. doi:10.1242/jcs.099879. PMID 22767506. 
  20. ^ Germann S, Gratadou L, Zonta E, Dardenne E, Gaudineau B, Fougère M, Samaan S, Dutertre M, Jauliac S, Auboeuf D (January 2012). "Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor". Oncogene 31 (42): 4536–49. doi:10.1038/onc.2011.618. PMID 22266867. 
  21. ^ Yan L, Borregaard N, Kjeldsen L, Moses MA (October 2001). "The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL". J. Biol. Chem. 276 (40): 37258–65. doi:10.1074/jbc.M106089200. PMID 11486009. 
  22. ^ Fernández CA, Yan L, Louis G, Yang J, Kutok JL, Moses MA (August 2005). "The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients". Clin. Cancer Res. 11 (15): 5390–5. doi:10.1158/1078-0432.CCR-04-2391. PMID 16061852. 
  23. ^ Costa D Lazzarini E et al. (November 2013). "Altered bone development and turnover in transgenic mice over-expressing lipocalin-2 in bone.". J. Cell. Phis. 228 (11): 2210–21. doi:10.1002/jcp.24391. PMID 23606520. 
  24. ^ a b Lippi G, Aloe R, Storelli A, Cervellin G, Trenti T (September 2012). "Evaluation of NGAL Test™, a fully-automated neutrophil gelatinase-associated lipocalin (NGAL) immunoassay on Beckman Coulter AU 5822". Clin. Chem. Lab. Med. 50 (9): 1581–4. doi:10.1515/cclm.2011.839. PMID 22962213. 
  25. ^ Krawczeski CD, Woo JG, Wang Y, Bennett MR, Ma Q, Devarajan P (June 2011). "Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass". J. Pediatr. 158 (6): 1009–1015.e1. doi:10.1016/j.jpeds.2010.12.057. PMID 21300375. 
  26. ^ a b c Uttenthal, L.O (April 2007). "NGAL: How Useful Is the New Marker of Kidney Damage?". CLI. 
  27. ^ "ARCHITECT Urine NGAL" (pdf). Abbott Diagnostics Europe. 
  28. ^ "Alere Triage NGAL Test" (pdf). Product Insert. Alere Ltd. 2012. 

Further reading[edit]

  • Triebel S, Bläser J, Reinke H, Tschesche H (1993). "A 25 kDa alpha 2-microglobulin-related protein is a component of the 125 kDa form of human gelatinase". FEBS Lett. 314 (3): 386–8. doi:10.1016/0014-5793(92)81511-J. PMID 1281792. 
  • Bläser J, Triebel S, Tschesche H (1995). "A sandwich enzyme immunoassay for the determination of neutrophil lipocalin in body fluids". Clin. Chim. Acta 235 (2): 137–45. doi:10.1016/0009-8981(95)06020-7. PMID 7554268. 
  • Bartsch S, Tschesche H (1995). "Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cells". FEBS Lett. 357 (3): 255–9. doi:10.1016/0014-5793(94)01303-I. PMID 7835423. 
  • Xu SY, Carlson M, Engström A et al. (1995). "Purification and characterization of a human neutrophil lipocalin (HNL) from the secondary granules of human neutrophils". Scand. J. Clin. Lab. Invest. 54 (5): 365–76. doi:10.3109/00365519409088436. PMID 7997842. 
  • Bundgaard JR, Sengeløv H, Borregaard N, Kjeldsen L (1994). "Molecular cloning and expression of a cDNA encoding NGAL: a lipocalin expressed in human neutrophils". Biochem. Biophys. Res. Commun. 202 (3): 1468–75. doi:10.1006/bbrc.1994.2096. PMID 8060329. 
  • Xu SY, Petersson CG, Carlson M, Venge P (1994). "The development of an assay for human neutrophil lipocalin (HNL)--to be used as a specific marker of neutrophil activity in vivo and vitro". J. Immunol. Methods 171 (2): 245–52. doi:10.1016/0022-1759(94)90044-2. PMID 8195592. 
  • Axelsson L, Bergenfeldt M, Ohlsson K (1996). "Studies of the release and turnover of a human neutrophil lipocalin". Scand. J. Clin. Lab. Invest. 55 (7): 577–88. doi:10.3109/00365519509110257. PMID 8633182. 
  • Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548. 
  • Stoesz SP, Friedl A, Haag JD et al. (1998). "Heterogeneous expression of the lipocalin NGAL in primary breast cancers". Int. J. Cancer 79 (6): 565–72. doi:10.1002/(SICI)1097-0215(19981218)79:6<565::AID-IJC3>3.0.CO;2-F. PMID 9842963. 
  • Coles M, Diercks T, Muehlenweg B et al. (1999). "The solution structure and dynamics of human neutrophil gelatinase-associated lipocalin". J. Mol. Biol. 289 (1): 139–57. doi:10.1006/jmbi.1999.2755. PMID 10339412. 
  • Friedl A, Stoesz SP, Buckley P, Gould MN (1999). "Neutrophil gelatinase-associated lipocalin in normal and neoplastic human tissues. Cell type-specific pattern of expression". Histochem. J. 31 (7): 433–41. doi:10.1023/A:1003708808934. PMID 10475571. 
  • Rudd PM, Mattu TS, Masure S et al. (1999). "Glycosylation of natural human neutrophil gelatinase B and neutrophil gelatinase B-associated lipocalin". Biochemistry 38 (42): 13937–50. doi:10.1021/bi991162e. PMID 10529240. 
  • Goetz DH, Willie ST, Armen RS et al. (2000). "Ligand preference inferred from the structure of neutrophil gelatinase associated lipocalin". Biochemistry 39 (8): 1935–41. doi:10.1021/bi992215v. PMID 10684642. 
  • Dias Neto E, Correa RG, Verjovski-Almeida S et al. (2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3491–6. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800. 
  • Zerega B, Cermelli S, Michelis B et al. (2000). "Expression of NRL/NGAL (neu-related lipocalin/neutrophil gelatinase-associated lipocalin) during mammalian embryonic development and in inflammation". Eur. J. Cell Biol. 79 (3): 165–72. doi:10.1078/S0171-9335(04)70019-9. PMID 10777108. 
  • Devireddy LR, Teodoro JG, Richard FA, Green MR (2001). "Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation". Science 293 (5531): 829–34. doi:10.1126/science.1061075. PMID 11486081.