Discovery of a novel pathway for catecholamines metabolism and in therapeutic utility in cardiac and renal disease
Renalase is a novel renal hormone that was discovered in our laboratory. It is synthesized by the proximal tubule and secreted in plasma where it metabolizes catecholamines and signals via a receptor-mediated pathway to enhance cell survival. Renalase deficiency aggravates renal and cardiac ischemic injury, and administration of recombinant renalase protects against ischemic and toxic acute kidney injury (AKI) and myocardial necrosis. Single nucleotide polymorphisms of the renalase gene are associated with essential hypertension, stroke and type 1 diabetes. We are currently investigating the molecular mechanisms mediating the direct cellular protective effect of renalase, its utility as a therapeutic agent for ischemic and toxic AKI, and as a potential biomarker for AKI.
Identification and validation of therapeutic targets for the treatment of obesity and diabetes
Voltage-gated potassium (Kv) channels regulate cell membrane potential and control a variety of cellular processes including insulin secretion. We found that the voltage-gated channel Kv1.3 and its signaling cascade represented a novel, pathway that regulates body weight and peripheral glucose metabolism. Inhibitors of Kv1.3 could prove useful in the management of obesity and diabetes.
Extensive Research Description
Molecular mechanims of renalase and its utility as a therapeutic agent in kidney injury
- Wang, L., Velazquez, H., Moeckel, G., Chang, J., Ham, A., Lee, HT., Safirstein, R., and Desir, G.V. 2014. Renalase prevents acute kidney injury via a receptor-mediated mechanism. Journal American Society of Nephrology. Online before Print; DOI:10.1681/asn
- Sizova, D, Velazquez, H, Sampaio-Maia, B, Quelhas-Santos, J, Pestana, M, Desir, G.V. 2013. Renalase regulates renal dopamine and phosphate metabolism. Am J Physiol Renal Physiol, 305: F839-844, 2013.
- Lee, H.T., Kim, J.Y., Kim, M., Wang, P., Tang, L., Baroni, S., D'Agati, V.D., and Desir, G.V. 2013. Renalase protects against ischemic AKI. Journal of the American Society of Nephrology 24:445-455.
- Desir, G.V., Tang, L., Wang, P., Li, G., Sampaio-Maia, B., Quelhas-Santos, J., Pestana, M., and Velazquez, H. 2012. Renalase lowers ambulatory blood pressure by metabolizing circulating adrenaline. Journal of the American Heart Association 1:e002634
- Wu, Y., Xu, J., Velazquez, H., Wang, P., Li, G., Liu, D., Sampaio-Maia, B., Quelhas-Santos, J., Russell, K., Russell, R., et al. 2011. Renalase deficiency aggravates ischemic myocardial damage. Kidney International 79:853-860
- Farzaneh-Far, R., Desir, G.V., Na, B., Schiller, N.B., and Whooley, M.A. 2010. A functional polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, dysfunction, and ischemia: data from the heart and soul study. PloS one 5:e13496
- Xu, J., Li, G., Wang, P., Velazquez, H., Yao, X., Li, Y., Wu, Y., Peixoto, A., Crowley, S., and Desir, G.V. 2005. Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. The Journal of Clinical Investigation 115:
- Xu, J., Wang, P., Li, Y., Li, G., Kaczmarek, L.K., Wu, Y., Koni, P.A., Flavell, R.A., and Desir, G.V. 2004. The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity. Proceedings of the National Academy of Sciences of the United S
- Xu, J., Koni, P.A., Wang, P., Li, G., Kaczmarek, L., Wu, Y., Li, Y., Flavell, R.A., and Desir, G.V. 2003. The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight. Human Molecular Genetics 12:551-559