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The Tamm–Horsfall glycoprotein (THP), also known as uromodulin, is a glycoprotein that in humans is encoded by the UMOD gene.^[1]^[2] Uromodulin is the most abundant protein excreted in ordinary urine.^[3]

Gene

The human UMOD gene is located on chromosome 16. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same isoform.^[2]

Protein

THP is a GPI-anchored glycoprotein. It is not derived from blood plasma but is produced by the thick ascending limb of the loop of Henle of the mammalian kidney. While the monomeric molecule has a MW of approximately 68 kDa, it is physiologically present in urine in large aggregates of up to several million Da.^[3] When this protein is concentrated at low pH, it forms a gel. Uromodulin represents the most quantitative protein in normal human urine (results based on MSMS determinations).^[4] It is the matrix of urinary casts derived from the secretion of renal tubular cells.

Function

Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. The excretion of uromodulin in urine may provide defense against urinary tract infections caused by uropathogenic bacteria.^[2]

The function of THP is not well understood. Studies using THP deficient mice revealed that THP may have a role in regulatory physiology and actually participates in transporter function.^[5] A role in bacterial binding and sequestration is suggested by studies showing that Escherichia coli which express MS (mannose-sensitive) pili or fimbriae (also fimbria, from the Latin word for "fringe") can be trapped by Tamm–Horsfall protein via its mannose-containing side chains.^[3] THP may also be important in protection from kidney injury by down-regulating inflammation.^[6]

Clinical significance

Uropontin, nephrocalcin and uromodulin (this protein) are the three known urinary glycoproteins that affect the formation of calcium-containing kidney stones or calculus. Tamm–Horsfall protein is part of the matrix in renal calculi but a role in kidney stone formation remains debatable. However, decreased levels of Tamm–Horsfall in urine have been found to be a good indicator of kidney stones.^[3]

Defects in this gene are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN). These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive renal failure.^[2]

Antibodies to Tamm–Horsfall protein have been seen in various forms of nephritis (e.g., Balkan nephropathy), however, it remains unclear whether there is any pathophysiologic relevance to these findings.^[7]

In multiple myeloma, there is often protein cast in the distal convoluted tubule and collecting duct of the kidneys, mainly consisting of immunoglobulin light chain known as Bence Jones protein, but often also contain Tamm–Horsfall protein.^[8]^[9]

History

The glycoprotein was first purified by Igor Tamm and Frank Horsfall from the urine of healthy individuals.^[10] It was later detected in the urine of all mammals studied.

In January 2016, its 3D structure was determined for the first time by researchers at Karolinska Institute.^[11]

References

^ Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C (Mar 1993). "Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11". Cytogenet Cell Genet 62 (4): 185–7. doi:10.1159/000133470. PMID 8382593.
^ ^a ^b ^c ^d "Entrez Gene: UMOD uromodulin (uromucoid, Tamm–Horsfall glycoprotein)".
^ ^a ^b ^c ^d Lau WH, Leong WS, Ismail Z, Gam LH (2008). "Qualification and application of an ELISA for the determination of Tamm Horsfall protein (THP) in human urine and its use for screening of kidney stone disease". Int. J. Biol. Sci. 4 (4): 215–22. doi:10.7150/ijbs.4.215. PMC 2500153. PMID 18695745.
^ Nagaraj N, Mann M (February 2011). "Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome". J. Proteome Res. 10 (2): 637–45. doi:10.1021/pr100835s. PMID 21126025.
^ Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, Luft FC, Alenina N, Bader M, Thiele BJ, Prasadan K, Raffi HS, Kumar S (2005). "Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice". Am. J. Physiol. Renal Physiol. 288 (3): F559–67. doi:10.1152/ajprenal.00143.2004. PMID 15522986.
^ El-Achkar TM, Wu XR, Rauchman M, McCracken R, Kiefer S, Dagher PC. Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am J Physiol Renal Physiol. 2008 Aug;295(2):F534-44. doi: 10.1152/ajprenal.00083.2008. Epub 2008 May 21. PMID 18495803
^ Vizjak A, Trnacević S, Ferluga D, Halilbasić A (November 1991). "Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology". Kidney Int. Suppl. 34: S68–74. PMID 1762338.
^ Abbas AK, Gerber R, Mitchell RS, Kumar V, Fausto N (2006). Pocket companion to Robbins and Cotran Pathologic Basis of Disease (7th ed.). Philadelphia, Pa: Saunders, Elsevier. p. 353. ISBN 0-7216-0265-7.
^ Aster JC (2007). "The Hematopoietic and Lymphoid Systems". In Kumar V, Abbas AK, Fauso N, Mitchell R. Robbins Basic Patholog (8 ed.). Philadelphia, PA: Saunders/Elsevier. p. 455. ISBN 1-4160-2973-7.
^ Tamm I, Horsfall FL (January 1952). "A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses". J. Exp. Med. 95 (1): 71–97. doi:10.1084/jem.95.1.71. PMC 2212053. PMID 14907962.
^ http://m.medicalxpress.com/news/2016-01-3d-images-reveal-body-guardian.html

External links

GeneReviews/NCBI/NIH/UW entry on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
OMIM entries on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
Tamm–Horsfall protein deposition

UpToDate Contents

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1. 常染色体優性尿細管間質性腎臓病（髄質嚢胞性腎疾患） autosomal dominant tubulointerstitial kidney disease medullary cystic kidney disease
2. 腎疾患の診断における尿検査 urinalysis in the diagnosis of kidney disease
3. 小児における蛋白尿の評価 evaluation of proteinuria in children
4. Treatment and prognosis of kidney disease in multiple myeloma and other monoclonal gammopathies
5. 成人におけるカルシウム結石の危険因子 risk factors for calcium stones in adults

English Journal

Hypertension: Uromodulin identified as a potential therapeutic target.

Kirk R.
Nature reviews. Nephrology.Nat Rev Nephrol.2014 Jan;10(1):2. doi: 10.1038/nrneph.2013.241. Epub 2013 Nov 19.
PMID 24247288

Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension.

Graham LA, Padmanabhan S, Fraser NJ, Kumar S, Bates JM, Raffi HS, Welsh P, Beattie W, Hao S, Leh S, Hultstrom M, Ferreri NR, Dominiczak AF, Graham D, McBride MW.Author information Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.AbstractA recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na+ excretion and further Na+ loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.
Hypertension.Hypertension.2013 Dec 9. [Epub ahead of print]
A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantl
PMID 24324041

Elucidation of the distal convoluted tubule transcriptome identifies new candidate genes involved in renal Mg2+ handling.

de Baaij JH, Groot Koerkamp MJ, Lavrijsen M, van Zeeland F, Meijer H, Holstege FC, Bindels RJ, Hoenderop JG.Author information Dept. of Physiology (286 Radboud Univ. Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101, Nijmegen 6500 HB, The Netherlands. J.Hoenderop@fysiol.umcn.nl.AbstractThe kidney plays a key role in the maintenance of Mg(2+) homeostasis. Specifically, the distal convoluted tubule (DCT) is instrumental in the fine-tuning of renal Mg(2+) handling. In recent years, hereditary Mg(2+) transport disorders have helped to identify important players in DCT Mg(2+) homeostasis. Nevertheless, several proteins involved in DCT-mediated Mg(2+) reabsorption remain to be discovered, and a full expression profile of this complex nephron segment may facilitate the discovery of new Mg(2+)-related genes. Here, we report Mg(2+)-sensitive expression of the DCT transcriptome. To this end, transgenic mice expressing enhanced green fluorescent protein under a DCT-specific parvalbumin promoter were subjected to Mg(2+)-deficient or Mg(2+)-enriched diets. Subsequently, the Complex Object Parametric Analyzer and Sorter allowed, for the first time, isolation of enhanced green fluorescent protein-positive DCT cells. RNA extracts thereof were analyzed by DNA microarrays comparing high versus low Mg(2+) to identify Mg(2+) regulatory genes. Based on statistical significance and a fold change of at least 2, 46 genes showed differential expression. Several known magnesiotropic genes, such as transient receptor potential cation channel, subfamily M, member 6 (Trpm6), and Parvalbumin, were upregulated under low dietary Mg(2+). Moreover, new genes were identified that are potentially involved in renal Mg(2+) handling. To confirm that the selected candidate genes were regulated by dietary Mg(2+) availability, the expression levels of solute carrier family 41, member 3 (Slc41a3), pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1α (Pcbd1), TBC1 domain family, member 4 (Tbc1d4), and uromodulin (Umod) were determined by RT-PCR analysis. Indeed, all four genes show significant upregulation in the DCT of mice fed a Mg(2+)-deficient diet. By elucidating the Mg(2+)-sensitive DCT transcriptome, new candidate genes in renal Mg(2+) handling have been identified.
American journal of physiology. Renal physiology.Am J Physiol Renal Physiol.2013 Dec;305(11):F1563-73. doi: 10.1152/ajprenal.00322.2013. Epub 2013 Oct 2.
The kidney plays a key role in the maintenance of Mg(2+) homeostasis. Specifically, the distal convoluted tubule (DCT) is instrumental in the fine-tuning of renal Mg(2+) handling. In recent years, hereditary Mg(2+) transport disorders have helped to identify important players in DCT Mg(2+) homeostas
PMID 24089412

Japanese Journal

ウロモジュリン遺伝子に新規変異G210Dが同定された家族性若年性高尿酸血症性腎症の1家系

大森さゆ,前山克博,佐藤清二
日本小児科学会雑誌 = The journal of the Japan Pediatric Society 116(12), 1892-1897, 2012-12
NAID 40019533319

The complex of immunoglobulin A and uromodulin as a diagnostic marker for immunoglobulin A nephropathy

OBARA Takashi,MIZOGUCHI Sadaaki,SHIMOZURU Tasunori,SATO Toshitaka,HOTTA Osamu
Clinical and experimental nephrology 16(5), 713-721, 2012-10-01
NAID 10031122258

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

HAN Jia,CHEN Yuqing,LIU Ying,LIANG Yu,WANG Xingyu,LIU Lisheng,WANG Fang,ZHANG Luxia,ZHANG Hong,WANG Haiyan
Hypertension research : clinical and experimental : official journal of the Japanese Society of Hypertension 35(7), 769-774, 2012-07-01
NAID 10030957105

Related Pictures

★リンクテーブル★

リンク元	「ウロモジュリン」
拡張検索	「neuromodulin」

「ウロモジュリン」

Uromodulin
Identifiers
Symbols	UMOD ; ADMCKD2; FJHN; HNFJ; HNFJ1; MCKD2; THGP; THP
External IDs	OMIM: 191845 MGI: 102674 HomoloGene: 2522 GeneCards: UMOD Gene
Gene ontology
Molecular function	• calcium ion binding; • IgG binding;
Cellular component	• spindle pole; • basolateral plasma membrane; • apical plasma membrane; • extrinsic component of membrane; • anchored component of membrane; • ciliary membrane; • extracellular exosome; • primary cilium;
Biological process	• cellular defense response; • heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules; • leukocyte cell-cell adhesion; • excretion; • negative regulation of cell proliferation; • chemical homeostasis; • metanephric ascending thin limb development; • metanephric distal convoluted tubule development; • metanephric thick ascending limb development; • neutrophil migration; • regulation of ion homeostasis;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

英: uromodulin
同: ウロムコイド uromucoid

「neuromodulin」

　　[★]

ニューロモジュリン

関: GAP-43、GAP-43 protein

[pmid8382593-1] Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C (Mar 1993). "Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11". Cytogenet Cell Genet 62 (4): 185–7. doi:10.1159/000133470. PMID 8382593.

[entrez-2] "Entrez Gene: UMOD uromodulin (uromucoid, Tamm–Horsfall glycoprotein)".

[Lau_2008-3] Lau WH, Leong WS, Ismail Z, Gam LH (2008). "Qualification and application of an ELISA for the determination of Tamm Horsfall protein (THP) in human urine and its use for screening of kidney stone disease". Int. J. Biol. Sci. 4 (4): 215–22. doi:10.7150/ijbs.4.215. PMC 2500153. PMID 18695745.

[Nagaraj_Mann_2011-4] Nagaraj N, Mann M (February 2011). "Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome". J. Proteome Res. 10 (2): 637–45. doi:10.1021/pr100835s. PMID 21126025.

[pmid15522986-5] Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, Luft FC, Alenina N, Bader M, Thiele BJ, Prasadan K, Raffi HS, Kumar S (2005). "Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice". Am. J. Physiol. Renal Physiol. 288 (3): F559–67. doi:10.1152/ajprenal.00143.2004. PMID 15522986.

[6] El-Achkar TM, Wu XR, Rauchman M, McCracken R, Kiefer S, Dagher PC. Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am J Physiol Renal Physiol. 2008 Aug;295(2):F534-44. doi: 10.1152/ajprenal.00083.2008. Epub 2008 May 21. PMID 18495803

[pmid1762338-7] Vizjak A, Trnacević S, Ferluga D, Halilbasić A (November 1991). "Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology". Kidney Int. Suppl. 34: S68–74. PMID 1762338.

[isbn0-7216-0265-7-8] Abbas AK, Gerber R, Mitchell RS, Kumar V, Fausto N (2006). Pocket companion to Robbins and Cotran Pathologic Basis of Disease (7th ed.). Philadelphia, Pa: Saunders, Elsevier. p. 353. ISBN 0-7216-0265-7.

[Robbins-9] Aster JC (2007). "The Hematopoietic and Lymphoid Systems". In Kumar V, Abbas AK, Fauso N, Mitchell R. Robbins Basic Patholog (8 ed.). Philadelphia, PA: Saunders/Elsevier. p. 455. ISBN 1-4160-2973-7.

[pmid14907962-10] Tamm I, Horsfall FL (January 1952). "A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses". J. Exp. Med. 95 (1): 71–97. doi:10.1084/jem.95.1.71. PMC 2212053. PMID 14907962.

[11] ttp://m.medicalxpress.com/news/2016-01-3d-images-reveal-body-guardian.html

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uromodulin