Effect of the chronic inhibition of endothelin-1 receptor in key factors of the chronic kidney injury (CKI) progression, diabetes and hypertension in an experimental model in vivo and in vitro

Abstract

Diabetes Mellitus (DM) and hypertension are the leading causes of chronic kidney disease. Diabetic nephropathy, as a result of chronic hyperglycemia, affects about 40% of diabetic patients and it is a major cause of morbidity and mortality among them. Hypertension is another important risk factor for chronic kidney disease, because it alters the intra-renal microcirculation, as well as metabolism. The progressive renal damage leads to the development of end-stage renal disease, the development of glomerulosclerosis, tubulointerstitial damage and proteinuria. The damage caused by chronic hyperglycemia and hypertension is caused by the production of reactive oxygen species, so different antioxidants have been tested. Endothelin-1 has inflammatory, proliferative and fibrotic kidney actions and it is produced in almost all kidney cells. Various stimuli do increase its production. Endothelin-1 receptor blockade have anti-inflammatory and antifibrotic effects, possibly in part by inhibiting the production of reactive oxygen species. The objective of this project is to analyze the effect of Macitentan, a new nonspecific antagonist of endothelin-1 receptor, in vivo experimental models of type I diabetes and hypertension, as well as in cultured mesangial cells exposed to high glucose concentrations, both extremely involved in matrix production during chronic exposure to glucose. (AU)