Abstract 384: Nov/ccn3: A Potential Antagonist of Angiotensin Ii Effects in Kidney Disease
Progression of chronic kidney disease (CKD) represents a constant challenge for the identification of new therapeutic targets. The NOV/CCN3 matricellular protein, belonging to the CCN (CYR61/CCN1, CTGF/CCN2, NOV/CCN3) family, could represent a new endogenous inhibitor of the fibrotic process that plays a crucial role in tissue damage and regression of renal function. However, the relation between NOV and renal disease remains unclear. Our objective was to study whether alterations in renal NOV expression are involved in the progression of CKD. NOV mRNA expression was significantly induced by 2.5-3 fold at 12-16 weeks in renin-transgenic mice (RenTg), a well established model of AngII-mediated nephropathy, through the Angiotensin receptor 1 (AT1R) compared to normotensive control animals (n=7 mice per group, p<0.05). NOV immunodetection revealed an up-regulation mainly in vascular smooth muscle cells (VSMC) in the renal cortex of RenTg mice. Interestingly, NOV expression was inversely correlated to known fibrotic markers such as Connective tissue growth factor, Transforming growth factor and collagen I, during the progression of renal disease in RenTg mice. NOV up-regulation at mRNA and protein levels (∼ 2.5 fold p<0.05) by AngII through AT1R was also observed in VSMC cultures. Furthermore, infection of these cells with an adenovirus recombinant for NOV strongly repressed in a dose-dependent manner the expression of the Angiotensin Receptor 1 reaching 72 and 78% (p<0.05) at mRNA and protein levels respectively. Treatment with exogenous NOV gave similar results. Conversely, knocking down NOV by small interfering RNA increased Angiotensin Receptor 1 by ∼3.5 to 4.5 fold and by ∼7.5 fold (p<0.05) at mRNA and protein levels respectively. These results indicate that NOV is involved in an AngII- AT1R regulatory loop. In subsequent studies the NOV-induced downregulation of AT1R was abrogated by integrin β1 specific siRNAs. Thus, NOV can attenuate the deleterious profibrotic effects of AngII during the progression of CKD and may provide a potential therapeutic option against this pathology.
- © 2012 by American Heart Association, Inc.