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renalase,
FAD-dependent amine oxidase
Identifiers
Symbols RNLS; RENALASE; FLJ11218
External IDs OMIM609360 MGI96621 HomoloGene4051 GeneCards: RNLS Gene
EC number 1.4.-.-
Orthologs
Species Human Mouse
Entrez 55328 67795
Ensembl ENSG00000184719 ENSMUSG00000071573
UniProt Q5VYX0 n/a
RefSeq (mRNA) NM_018363 XM_001481327
RefSeq (protein) NP_001026879 XP_001481368
Location (UCSC) Chr 10:
90.02 - 90.33 Mb
Chr 19:
33.21 - 33.47 Mb
PubMed search [1] [2]

The renalase protein is an enzyme which breaks down catecholamines like adrenaline (epinephrine) and noradrenaline (norepinephrine) in the blood circulation.[1][2] Researchers at Yale School of Medicine who discovered and named renalase in 2005[3] suggest that the human kidney releases this protein into the bloodstream to regulate blood pressure (in addition to other possible, as yet undiscovered, functions).[1]

Analysis of its structure shows that it is an FAD-dependent amine oxidase. The gene encoding this protein is called RNLS (also known as C10orf59 or FLJ11218).[4]

Structure

The renalase protein consists of a secretory signal peptide, a flavin adenine dinucleotide (FAD)-binding region, and an amine oxidase domain. At least four alternative splicing isoforms have been identified in humans (hRenalase1 to hRenalase4). Only hRenalase1 is detected in human blood samples, which means that hRenalase2 to 4 probably have a different function than hRenalase1.[1]

Function

Renalase levels are markedly reduced in patients with severe chronic kidney disease (end-stage renal disease, ESRD). Since hormones like erythropoietin are secreted less in ESRD, the scientists who discovered renalase believe that it might also be a kidney hormone, although it is also expressed in heart muscle, skeletal muscle and liver cells in humans, and in mouse testicles.[1][5] In a rat model of chronic kidney disease (in which 85% of kidney tissue is surgically removed), renalase deficiency and defective renalase activation develops 2-3 weeks after surgery.[6]

Renalase degrades catecholamines, which are hormones involved in the acute stress (fight-or-flight) response. Injection of renalase in rodents transiently decreases blood pressure, heart rate, heart muscle contractility, and blood vessel resistance.[3] Under normal conditions, renalase is present but inactive in the bloodstream. When catecholamines are released into the bloodstream however, renalase activity increases about tenfold within 30 seconds, and remains high for an hour or longer. Activation of circulating renalase is probably responsible for early activation, while secretion into the bloodstream occurs after 15 minutes.[6]

Using small inhibitory RNAs or knock-out mice, the consequences of loss of renalase function have been studied. These include raised blood pressure (hypertension), increased heart rate (tachycardia), increased blood vessel resistance (vasoconstriction) and an increased catecholamine response.[7][8]

A genetic association study in a Han Chinese population suggested that common genetic differences (polymorphisms) in the renalase gene are a risk factor for essential hypertension.[9]

Since renalase is expressed in heart muscle and norepinephrine is thought to aggravate heart attacks (myocardial infarction), researchers studied whether renalase could protect against myocardial infarction. If mouse hearts were exposed to oxygen shortage (ischemia), myocardial infarction size was decreased and heart function better preserved when renalase was administered.[10] Renalase knock-out mice are also more sensitive to damage to the heart muscle.[1] Renalase expression in the heart is also decreased in the rat model of end-stage renal disease. The scientists who discovered renalase believe that it might explain some of the susceptibility to heart disease among patients with chronic kidney disease.[1]

Footnotes

  1. ^ a b c d e f Desir GV (May 2009). "Regulation of blood pressure and cardiovascular function by renalase". Kidney Int.. doi:10.1038/ki.2009.169. PMID 19471322. http://dx.doi.org/10.1038/ki.2009.169.  
  2. ^ Boomsma F, Tipton KF (2007). "Renalase, a catecholamine-metabolising enzyme?". J Neural Transm 114 (6): 775–6. doi:10.1007/s00702-007-0672-1. PMID 17385068. http://dx.doi.org/10.1007/s00702-007-0672-1.  
  3. ^ a b Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, Wu Y, Peixoto A, Crowley S, Desir GV (May 2005). "Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure". J. Clin. Invest. 115 (5): 1275–80. doi:10.1172/JCI24066. PMID 15841207. PMC 1074681. http://dx.doi.org/10.1172/JCI24066.  
  4. ^ RNLS renalase, FAD-dependent amine oxidase. Entrez Gene. Accessed July 31, 2009.
  5. ^ Wang J, Qi S, Cheng W, Li L, Wang F, Li YZ, Zhang SP (December 2008). "Identification, expression and tissue distribution of a renalase homologue from mouse". Mol. Biol. Rep. 35 (4): 613–20. doi:10.1007/s11033-007-9131-1. PMID 17846919. http://dx.doi.org/10.1007/s11033-007-9131-1.  
  6. ^ a b Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, Desir GV (March 2008). "Catecholamines regulate the activity, secretion, and synthesis of renalase". Circulation 117 (10): 1277–82. doi:10.1161/CIRCULATIONAHA.107.732032. PMID 18299506. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=18299506.  
  7. ^ Ghosh SS, Gehr TWB, Sica DA et al. Effect of renalase inhibition on blood pressure. J Am Soc Nephrology 2006; 17: 208A.
  8. ^ Desir GV, Wu Y, Wang P et al. Renalase deficiency increases sympathetic tone and causes hypertension. J Am Soc Nephrol 2008. Available at http://www.asn-online.org/education_and_meetings/renal_week/archives/
  9. ^ Zhao Q, Fan Z, He J, Chen S, Li H, Zhang P, Wang L, Hu D, Huang J, Qiang B, Gu D (August 2007). "Renalase gene is a novel susceptibility gene for essential hypertension: a two-stage association study in northern Han Chinese population". J. Mol. Med. 85 (8): 877–85. doi:10.1007/s00109-006-0151-4. PMID 17216203. http://dx.doi.org/10.1007/s00109-006-0151-4.  
  10. ^ Desir GV, Li Y, Liu D et al. Downregulation of cardiac renalase expression in CKD, and protective effect of renalase in acute coronary syndrome. J Am Soc Nephrol 2007; 18: 149A.
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