CX43-CRF · Implication of connexin 43 in chronic renal failure

Chronic renal failure (CRF), one of the main causes of disability in western societies, is promoted by a variety of factors including hypertension, diabetes, ischemic, immunological and toxic injury. These factors are linked by their common ability to promote chronic inflammation and fibrosis leading to decline of renal function. Dialysis and transplantation are the only available options that allow survival of patients. Arresting the progression of CRF is one of the major challenges of public health today. Alterations of the expression of the gap junction protein connexin 43 (Cx43) have been associated to the development of inflammation in chronic vascular pathologies. Thus, Cx43 expression was increased during atherogenesis, whereas Cx43 inhibition protected vessels from the development of atherosclerotic plaque. An up-regulation of the Cx43 expression has been also reported in renal inflammation and hypertension suggesting that this connexin may be involved in renal disease. In this project we intend to study the role of Cx43 in CRF and to propose treatments and diagnostic tools targeting this protein to protect against the disease. Thus, in our project: i) we will use the RenTg mice, expressing high steady levels of renin, to study modulation of Cx43 expression during progression of hypertension-induced renal disease; ii) Cx43-specific blockers will be administer to RenTg mice to see whether decreasing Cx43 expression could reverse the decline of renal function. Cx43 expression will be also reduced genetically by interbreeding the RenTg with the Cx43+/- mice; iii) we will attempt to delineate molecular mechanisms involving Cx43 regulation in endothelial cells in vitro under angiotensin II treatment, a peptide known to participate to renal vascular fibrosis. As perspectives, we will transfer knowledge obtained from this project in humans by testing renal biopsies. Thus, we hope to establish a correlation between Cx43 expression and human CRF.