Feedback regulation of catecholamines levels through an enzyme called renalase
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March 1, 2008 By Benjamin A. Olenchock, M.D. Ph.D. [1]
New Haven, CT
The kidneys secrete and enzyme called renalase, which is an amine oxidase capable of metabolizing catacholamines. Interestingly, patients with chronic kidney disease have diminished circulating levels of this enzyme. It is possible that lower levels of this enzyme might contribute to the cardiovascular risk associated with chronic kidney disease. Now, new work has demonstrated that renalase is activated by catecholamines, creating a negative feedback loop. A better understanding of this new pathway for regulation of catecholamine function might lead to new therapies to help ameliorate the cardiovascular risks of chronic kidney disease.
Researchers at Yale University published their findings in the journal Circulation. They measured renalase enzymatic activity by an amine oxidase assay. To determine the amine oxidase activity attributable to renalase, they performed the assay in the presence and absence of an antibody that blocks renalase activity and then calculate renalase activity. There is very little renalase activity in the blood at steady state, while activity in the urine is elevated. With parenteral administration of catacholamines, however, serum renalase activity increases within minutes. At later timepoints, gene expression and protein levels of renalase are also upregulated by catecholamines. In a mouse model of chronic kidney disease, renalase levels and activity are greatly down-regulated. The authors propose that renalase exists in a pro-enzymatic form in the blood and is activated directly or indirectly by elevated levels of catecholamines.
This work characterized a novel negative feedback pathway for regulation of catecholamine levels. As the authors note, this pathway might help to explain the heightened adrenergic tone in patients with chronic kidney disease, who have lower circulating levels of renalase. Additionally, it might explain why nephrectomy does not fix hypertension in CKD patients despite a beneficial lowering of angiotensin levels. The role of renalase in the hormonal regulation of vascular tone and cardiac contractility is just beginning to be understood. It is not clear from these studies how renalase is activated and whether catecholamines act directly or indirectly in this process. The authors conclude that the data thus far suggest a "causal" role of renalase deficiency in the hightened adrenergin tone and cardiovascular risk associated with chronic kidney disease. With the myriad of vascular problems associated with kidney disease this statement seems premature. Demonstration of improvement in adrenergic tone by renalase replacement would be a first step towards establishing a contribution of renalase deficiency. Future studies would also benefit from a more direct assay for renalase function – inferring specific enzymatic activity by the impact of a blocking enzyme is not ideal. This newly identified enzyme is attractive from a physiologic and therapeutic perspective as well. Perhaps in the future renalase will be a standard additive to dialysate to help regulate adrenergic tone in patients with end stage kidney disease.
REFERENCES
- Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, Desir GV. Catecholamines Regulate the Activity, Secretion, and Synthesis of Renalase. Circulation. 2008 Feb 25; [Epub ahead of print] PMID: 18299506
- Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, Wu Y, Peixoto A, Crowley S, Desir GV. Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest. 2005 May;115(5):1275-80. Epub 2005 Apr 7. PMID: 15841207
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