Bone Morphogenetic Proteins (BMPs) in renal response to injury: application of BMP-responsive element-reporter mice to monitor BMP-signalling in experimental renal fibrogenesis and its reversal
01 / 2006 - 12 / 2009
This project aims at elucidation of pathways critically involved in regenerative potential and reversal of fibrosis of the damaged kidney. Progression to end stage renal disease by fibrotic remodelling of the kidney is the major threat to patients with common renal diseases like diabetic nephropathy and hypertensive nephrosclerosis. Most likely, this seemingly autonomic process is related to the effect of profibrotic growth factors including CTGF and TGF-beta. Recently, reversal of renal fibrosis has been achieved in several experimental models including hypertension and diabetes mellitus (DM) by administration of BMP-7. This has generated hope for development of novel therapeutics applicable in human disease. From in vivo and in vitro studies we know that TGF-beta and BMPs share part of their signal transduction machinery and that the balance of BMP/TGF-beta signalling activity may be a decisive factor in pro- and anti-fibrotic processes. However, little is known about in vivo kinetics, targets and mechanisms involved in the beneficial effect of BMPs in the kidney. Since both TGF-beta- and BMP signalling are multifunctional and almost ubiquitous, such knowledge will be essential for translation of results from experimental models into human disease, and for development of pharmaceuticals specifically addressing kidney remodelling. In all experiments we will use a unique, recently generated transgenic mouse reporting canonical BMP signalling activity at the level of cellular detail to study kinetics and distribution of BMP signalling during fibrogenesis and its reversal. We will first study the effect of transfection (and of infusion) of CTGF (BMP-inhibitor) and of BMP-7 on in vivo reporter activity in healthy mice. Next, in STZ induced type-1 DM, in which fibrosis is already known to be reversed by BMP-7, we will analyze kinetics and distribution of BMP signalling activity during fibrogenesis and after transfection of pBMP-7. To probe more general applicability of our concept, we will also analyze BMP signalling activity in the NO inhibition model in which fibrosis is reversed by ET1-R blockade, a model in which involvement of BMP has not been investigated. Finally, we will investigate whether mechanisms by which altered BMP signalling affects progression and reversal of kidney damage can be identified by transcriptome analysis of specific tissue structures obtained by laser microdissection.