Cardiac remodeling is often accompanied by enhanced expression of the transcription factor AP-1. Involvement of this transcription factor in processes of cardiac remodeling, like hypertrophic growth and apoptosis, has already been demonstrated on the level of ventricular cardiomyocytes in vitro. Now, we analysed the influence of AP-1 on processes of cardiac remodeling in mice with unilateral kidney stenosis by overexpression of the AP-1 inhibitor JDP-2 in transgenic mice.

In 4 - 5 week old mice renal artery of left kidney was clipped. As control sham operated animals were used (sham). After 4 weeks animals were analysed. Stenosis resulted in atrophy of the left kidney (kidney/body weight: 0.0041 ± 0.0014 left vs. 0.0074 ± 0.0009 right kidney, p<0.05) and hypertension: In WT-mice as well as in JDP2-mice blood pressure increased from 120 ± 6 to 142 ± 16 mmHg and from 126 ± 5 to 156 ± 9 mmHg, respectively (p<0.05). Induction of hypertrophic growth, however, was seen in WT-animals only: Heart/body weight increased 4 weeks after stenosis to 111.6 ± 3.4% compared to sham WT-mice (p<0.05). As further sign for hypertrophic growth BNP-mRNA-expression was enhanced 6.0 ± 1.7-times vs. sham WT-mice (p<0.05). None of these hypertrophic parameters was increased in JDP2-mice after kidney stenosis. Expression of TGFb₁, that is known to be regulated by AP-1, was enhanced 3.4-times after stenosis in WT-mice (p<0.05). At the same time, mRNA of SMAD7, which is an inhibitory protein of TGFb₁-signaling, was enhanced 5.4-fold in WT-mice (p<0.05). Thus, at this disease state hearts of WT mice seem to counteract the pro-apoptotic and -fibrotic action of TGFb. This is reflected in enhanced expression of anti-apoptotic Bcl-2 mRNA and no significant change in fibrotic marker genes like collagen 1, elastin and fibronectin. In JDP2 mice neither TGFb₁ expression nor Bcl-2 and SMAD7 expression changed after renal stenosis. Concerning genes controlling calcium content and thus contractility of cardiomyocytes, SERCA-mRNA was reduced by 84% while phospholamban- (PLB) and NCX-mRNA was found upregulated 2,4- and 3.8-fold vs. sham WT-mice (p<0.05) In JDP2-mice reduction of SERCA-mRNA was also visible after kidney stenosis (0.41-fold, p<0,05). In contrast to WT-mice also PLB- and NCX-mRNA were downregulated 0.5-fold (p<0.05) and 0.47-fold (n.s.), respectively.

Conclusions: 4 weeks after kidney stenosis hypertrophic growth is induced in WT-mice. Overexpression of the AP-1 inihibitor JDP2 prevents this hypertrophic growth response. In addition, JDP-2 overexpression prevents induction of the pro-apoptotic and -fibrotic growth factor TGFb₁. Furthermore, in WT mice SERCA-mRNA is reduced, which indicates an impairment of contractile heart function after kidney stenosis. This decline in SERCA-mRNA could not be prevented by JDP2 overexpression.