CX43-CRF · Implication of connexin 43 in chronic renal failure
FP7 — People (Marie Curie Actions)
- Duration
- 2008-12-01 → 2010-11-30
- EU contribution
- €172,168
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
Implication of connexin 43 in chronic renal failure
Chronic renal failure (CRF) represents one of the major causes of disability in western countries due to population’s aging, improved survival from cardiovascular diseases and spreading of type-2 diabetes. In the European Union over 7 million people are reported to be affected by CRF. Three hundred thousand of these are already being treated with renal replacement therapy, either by dialysis or transplantation, and the number requiring such treatment is progressively increasing each year. The relentless decline of renal function can be slowed down by anti-hypertensive therapies but they are partially effective. Thus, development of more effective and specific treatments for progressive renal failure is required in order to stop the progressing number of people affected by the disease. The CRF process can be promoted by a variety of mechanisms including hypertension, diabetes or toxic injury. These pathologies may affect any of the kidney structures and are linked by their common ability to promote development of chronic inflammation leading to tissue sclerosis and to progressive decline of renal function. Inflammation and excessive scaring are complex processes and have been recently associated with disruptions of gap junction-mediated intercellular communication (GJIC). Gap junctions are composed of intercellular channels that allow the direct exchange of small molecules between adjacent cells, this way synchronizing responses in multi-cellular organisms. This type of intercellular communication permits rapidly coordinated activities such as contraction of cardiac muscle but plays also a crucial role in slower physiological processes such as cell growth and development. Gap junction channels are formed by members of a family of related proteins called connexins (Cx) in vertebrates. There are more than 20 different types of Cx in the human and mouse genomes. Each type of connexin-made channel has unique permeabilities to various molecules. Thus, Cx composition of gap junctions appeared to determine channel selectivity. Alterations of the expression of the major gap junction protein Cx43 have been associated to the development of inflammation in chronic vascular pathologies such as atherosclerosis. Inhibiting its expression protected vessels from the atherosclerotic plaque development and related diseases. However, little was known about the implication of this Cx in chronic renal pathologies. Thus the aim of our study was to investigate the role of Cx43 in an important degenerative pathology, the CRF. For this purpose, we used different models characterized by an inflammatory response leading to chronic kidney disease.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union