Chronic kidney disease affects millions of people in the U.S. and worldwide; however, current treatments are not highly effective. Many factors contribute to chronic kidney disease, including diabetes, hypertension, autoimmune disorders, and others. Research in the lab of University of Utah Health investigator Donald Kohan, MD, PhD, used genetically engineered mice to help identify a peptide, endothelin-1, and its receptor, ETA, as key regulators of blood pressure and kidney function in health. Kohan and his colleagues also helped determine that kidney ET-1 production is increased in many kidney diseases and, through activation of ETA receptors on most kidney cell types, leads to inflammation, scarring and decreased kidney function.
Together with national and international collaborators, they have translated these studies into clinical trials demonstrating that blocking the ETA receptor protects kidney function in individuals with type 2 diabetes mellitus. These trials with ETA receptor antagonists are now being extended into other forms of chronic kidney disease. Targeting the endothelin-1/ETA receptor system represents a promising approach to the treatment of chronic kidney disease.
Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention. Ahn D, Ge Y, Stricklett PK, Gill P, Taylor D, Hughes AK, Yanagisawa M, Miller L, Nelson RD, Kohan DE. J Clin Invest. 2004 Aug;114(4):504-511.
Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T, Audhya U, Andress DL. J Am Soc Nephrol. 2011 Apr;22(4):763-772.
Regulation of blood pressure and salt homeostasis by endothelin. Kohan DE, Inscho E, Rossi N, Pollock DM. Physio Rev. 2011 Jan;91(1):1-77.
Atrasentan and renal events in type 2 diabetes with chronic kidney disease (SONAR): a double-blind, randomized, placebo-controlled trial. Heerspink HJ, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou F-F, Kitzman DW, Kohan DE, Makino H, McMurray J, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D. Lancet. 2019 May;393(10184):1937-1947.