Uromodulin
| Uromodulin | ||
|---|---|---|
| Properties of human protein | ||
| Mass / length primary structure | 590 amino acids; 64.3 kDa | |
| Precursor | (640 aa) | |
| Isoforms | 3 | |
| Identifier | ||
| Gene names | UMOD ; FJHN; ADMCKD2; HNFJ; MCKD2; GHP | |
| External IDs | ||
| Occurrence | ||
| Parent taxon | Euteleostomi | |
| Orthologue | ||
| human | mouse | |
| Entrez | 7369 | 22242 |
| Ensemble | ENSG00000169344 | ENSMUSG00000030963 |
| UniProt | P07911 | Q8CJA0 |
| Refseq (mRNA) | NM_001008389 | NM_009470 |
| Refseq (protein) | NP_001008390 | NP_033496 |
| Gene locus | Chr 16: 20.25-20.27 Mb | Chr 7: 119.25 - 119.27 Mb |
| PubMed search | 7369 |
22242
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Uromodulin ( Tamm-Horsfall protein according to Igor Tamm (1922–1995) and Frank L. Horsfall (1906–1971)) is a protein that is excreted by the kidneys into the urine . It is the protein with the highest concentration in the urine (excretion around 50 mg / d). It is believed that uromodulin protects the kidneys from kidney stone formation and urinary tract infections .
genetics
Uromodulin is encoded by the UMOD gene.
education
Uromodulin is synthesized in cells of the thick ascending limb of Henle's loop and transported to the luminal cell membrane via glycosyl-phosphatidyl-inositol (GPI) . There it is proteolytically split and released into the lumen of the renal tubule . To a lesser extent it reaches the interstitium basolaterally . The mechanism and biological significance of the basolateral release are still unknown.
tasks
It is believed that uromodulin protects the kidney from kidney stone formation and urinary tract infections . Uromodulin has immunomodulatory properties and is able to activate neutrophil granulocytes and monocytes . Uromodulin activates dendritic cells via toll-like receptor -4 ( TLR4 ) and thus combines non-specific with specific immune defenses .
proof
Uromodulin can be detected both in urine and in blood serum or plasma using commercial ELISA methods.
Medical importance
Mutations in the uromodulin UMOD gene lead to three hereditary kidney diseases:
- Familial Juvenile Hyperuricemic Nephropathy (FJHM),
- Medullary cystic kidney disease type 2 ( Medullary Cystic Kidney Disease Type 2 , MCKD2) and
- Dominant glomerulozystische kidney disease ( Glomerulocystic Kidney Disease , GCKD).
In adolescents in particular, these mutations lead to inflammation ( tubulointerstitial nephritis ) and increased formation of connective tissue ( fibrosis ) in the renal medulla and to a reduced ability of the kidney to concentrate the urine more highly. In the case of FJHM, increased uric acid levels and gout are the main symptoms , in MCKD2 the formation of kidney cysts . In a genome-wide association study, mutations in the gene for uromodulin were linked to an increased likelihood of developing chronic kidney disease.
A decrease in the uromodulin concentration measured in serum is associated with a significant deterioration in kidney function. The latest evidence that uromodulin, as a kidney-specific glycoprotein from the epithelia of the thick ascending part of Henle's loop, not only circulates in the urine, but also in ng / ml in the serum, is based on a second transport route: the well-known, traditional transport of uromodulin takes place in the direction of the tubular lumen via the apical membrane. A second way, however, is towards the basolateral plasma membrane, whereby the protein is embedded in cytoplasmic vesicles. The vesicles fuse with the basal plasma membrane, uromodulin is released into the kidney interstitium and appears in the blood. The median serum concentration of healthy people, measured using a sensitive ELISA based on monoclonal antibodies, is 207 ng / ml. The serum concentrations of uromodulin drop progressively in renal insufficiency and are hardly measurable in the functional end stage or in dialysis patients. In contrast to traditional function markers such as serum creatinine, cystatin C and eGFR-cystatinC, the serum uromodulin level of healthy kidneys falls significantly earlier towards stage 1 renal insufficiency (CKD-1), therefore recognizing kidney involvement earlier than any other known measurement parameter of kidney function . Low serum concentrations of uromodulin are also predictive of later transplant dysfunction. Mutations in the UMOD gene are closely linked to the risk of renal insufficiency reaching the end stage of requiring dialysis. What is striking here is that healthy family members of a UMOD gene missense mutation also have very low blood levels of uromodulin. In 529 patients at increased cardiovascular risk, decreased serum uromodulin levels were associated with increased all-cause mortality; on the other hand those with higher values with a better metabolic situation, lower prevalence of further comorbidities such as arterial hypertension, diabetes mellitus and heart failure. Low serum uromodulin concentrations were also associated with increased all-cause mortality in 3,057 patients who underwent coronary angiography. In addition, arterial hypertension, diabetes mellitus, heart failure were associated with lower uromodulin levels in the blood, whereas higher serum uromodulin levels were associated with younger age, lower BMI (body mass index), lower blood pressure, lower triglycerides, lower fasting blood sugar, hemoglobin A-1c, highly sensitive C- reactive protein, parathyroid hormone, galectin-3, NT-proBNP, LDL and HDL cholesterol, but with higher 25- (OH) 2-vitamin D levels. The glomerular filtration rate (GFR) was directly correlated with the level of serum uromodulin, with dependencies on the genotype of the gene polymorphism SNP rs12917707: higher GFR for a given serum urodulin value could be attributed to the T / T genotype, the mean to the G / T and lower to the GG genotype assign.
In patients with multiple myeloma , the presence of Tamm-Horsfall protein can cause precipitation of light chains in the form of protein cylinders in the kidney tubules . These precipitates have a direct toxic effect on the cells of the kidney tubules and can lead to a rapid loss of kidney function and thus to acute kidney failure ( myeloma kidney ).
Web links
- Tamm-Horsfall-Protein Pathology - Pathopic image database of the University of Basel ( PathoPic - Instructions ; PDF; 2.2 MB)
- Tamm Horsfall Glycoprotein and Uromodulin: It Is All about the Tubules! Clinical Journal of the American Society of Nephrology 2016 Jan 7; 11 (1): 6-8.
swell
- P. Jennings et al .: Membrane Targeting and Secretion of Mutant Uromodulin in Familial Juvenile Hyperuricemic Nephropathy . In: J Am Soc Nephrol . No. 18 , 2007, p. 264-273 ( Article ).
Individual evidence
- ^ I. Tamm, FL Horsfall: A MUCOPROTEIN DERIVED FROM HUMAN URINE WHICH REACTS WITH INFLUENZA, MUMPS, AND NEWCASTLE DISEASE VIRUSES. In: Journal of Experimental Medicine. 95, 1951, pp. 71-97, doi: 10.1084 / jem.95.1.71 .
- ↑ Tarek M. El-Achkar, Xue-Ru Wu: Uromodulin in kidney injury: an instigator, bystander, or protector? In: American Journal of Kidney Diseases . tape 59 , no. 3 , March 1, 2012, p. 452-461 , doi : 10.1053 / j.ajkd.2011.10.054 , PMID 22277744 , PMC 3288726 (free full text).
- ↑ BioVendor R&D - Immunoassays \ Uromodulin Human ELISA. Retrieved December 15, 2016 .
- ↑ Anna Köttgen, Nicole L Glazer u. a .: Multiple loci associated with indices of renal function and chronic kidney disease. In: Nature Genetics. 41, 2009, p. 712, doi: 10.1038 / ng.377 .
- ↑ Lorenz Risch, Karl Lhotta, Dominik Meier, Pedro Medina-Escobar, Urs E. Nydegger: The serum uromodulin level is associated with kidney function . In: Clinical Chemistry and Laboratory Medicine . tape 52 , no. 12 , December 1, 2014, p. 1755-1761 , doi : 10.1515 / cclm-2014-0505 , PMID 24933630 .
- ↑ a b J. Scherberich, R. Gruber, WA Nockher et al: Serum uromodulin — a marker of kidney function and renal parenchymal integrity. In: Nephrology Dialysis Transplantation. 2017, doi: 10.1093 / ndt / gfw422 .
- ↑ D. Steubl, M. Block, V. Herbst, WA Nockher, W. Schlumberger, R. Satanovskij, S. Angermann, AL Hasenau, L. Stecher, U. Heemann, L. Renders, J. Scherberich: Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients. In: Medicine. Volume 95, number 10, March 2016, p. E3011, doi: 10.1097 / MD.0000000000003011 . PMID 26962815 , PMC 4998896 (free full text).
- ↑ Dominik Steubl, Matthias Block u. a .: Serum uromodulin predicts graft failure in renal transplant recipients. In: Biomarkers. 22, 2016, p. 171, doi: 10.1080 / 1354750X.2016.1252957 .
- ↑ R. Satanovskij, A. Bader, M. Block, V. Herbst, W. Schlumberger, T. Haack, WA Nockher, U. Heemann, L. Renders, C. Schmaderer, S. Angermann, M. Wen, T. Meitinger, J. Scherberich, D. Steubl: A new missense mutation in UMOD gene leads to severely reduced serum uromodulin concentrations - A tool for the diagnosis of uromodulin-associated kidney disease. In: Clinical biochemistry. Volume 50, number 3, February 2017, pp. 155-158, doi: 10.1016 / j.clinbiochem.2016.10.003 . PMID 27729211 .
- ↑ A. Leiherer, A. Muendlein, CH Saely, J. Ebner, EM Brandtner, P. Fraunberger, H. Drexel: Serum uromodulin is a predictive biomarker for cardiovascular events and overall mortality in coronary patients. In: International journal of cardiology. December 2016, doi: 10.1016 / j.ijcard.2016.12.183 . PMID 28089453 .
- ↑ a b c Graciela E. Delgado, Marcus E. Kleber u. a .: Serum Uromodulin and Mortality Risk in Patients Undergoing Coronary Angiography. In: Journal of the American Society of Nephrology. , S. ASN.2016111162, doi: 10.1681 / ASN.2016111162 .