Gene expression profiling on global cDNA arrays gives hints concerning potential signal transduction pathways involved in cardiac fibrosis of renal failure

Abstract

Cardiac remodelling with interstitial fibrosis in renal failure, which so far is only poorly understood on the molecular level, was investigated in the rat model by a global gene expression profiling analysis. Sprague-Dawley rats were subjected to subtotal nephrectomy (SNX) or sham operation (sham) and followed for 2 and 12 weeks, respectively. Heart-specific gene expression profiling, with RZPD Rat Unigene-1 cDNA arrays containing about 27 000 gene and EST sequences revealed substantial changes in gene expression in SNX compared to sham animals. Motor protein genes, growth and differentiation markers, and extracellular matrix genes were upregulated in SNX rats. Obviously, not only genes involved in cardiomyocyte hypertrophy, but also genes involved in the expansion of non-vascular interstitial tissue are activated very early in animals with renal failure. Together with earlier findings in the SNX model, the present data suggest the hypothesis that the local renin-angiotensin system (RAS) may be activated by at least two pathways: (a) via second messengers and Gproteins (short-term signalling); and (b) via motor proteins, actins and integrins (longterm signalling). The study documents that complex hybridization analysis yields reproducible and promising results of patterns of gene activation pointing to signalling pathways involved in cardiac remodelling in renal failure. The complete array data are available via http://www.rzpd.de/cgi-bin/services/exp/viewExpressionData.pl.cgi

Procollagen C-proteinase enhancer-1 (PCPE-1), a potential biomarker and therapeutic target for fibrosis

“…More generally, PCPE-1 has also been used to assess myocardial ECM remodelling, most of the time together with collagens I and III and with the cross-linking enzyme lysyl oxidase, and its up-regulation was for example demonstrated when MI in sedentary rats was compared to MI in exercised rats [108] , after subtotal nephrectomy in rats [117] or after ischemia–reperfusion injury in mice [118] and pigs [119] . All these results demonstrate that PCPE-1 overexpression broadly overlaps collagen overexpression and suggest a central role of PCPE-1 in both replacement and interstitial fibrosis of the heart.…”

Renal Failure is Associated with Driving of Gene Expression towards Cardiac Hypertrophy and Reduced Mitochondrial Activity

“…Amann et al have previously presented gene chip array data, pointing to cardiac hypertrophy after STN as early as two weeks post surgery [22]. They have shown that genes encoding for collagens and proteoglycans are upregulated two weeks post surgery, and that 10 weeks later (12 weeks post surgery), a striking upregulation in laminins and integrins is noted.…”