MO100WNT/Β-CATENIN SIGNALING PATHWAY IS ASSOCIATED WITH HYPERTENSIVE CARDIAC AND RENAL FIBROSIS

Abstract

Abstract Background and Aims Arterial hypertension (AH) causes a cardiac remodeling and renal fibrosis which considered to be mediated by reactivation of fetal and pro-fibrotic signaling pathways. Signal transduction of canonical Wnt (β-catenin expression) evaluation in the settings of heart and kidney hypertensive alterations was the subject of the study. Method Systolic blood pressure (BP), serum and urinary creatinine (Cr), proteinuria (uTP), inorganic phosphate (sPi), intact parathyroid hormone (PTH), intact fibroblast growth factor 23 (FGF23), Klotho protein, were estimated in spontaneously hypertensive rats after 1 (SHR1, n=6), 2 (SHR2, n=6), 4 (SHR4, n=6) и 6 (SHR6, n=6) months of exposure. Perivascular and interstitial fibrosis (Masson's trichrome), and β-catenin expression (IHC) were analyzed by light microscopy of myocardium and kidney tissues and calculated quantitatively. Statistical comparisons among groups were performed using Mann–Whitney U-test and Kruskal-Wallis H-test. The association between biochemical and morphological variables was estimated by Spearman’s correlation. Results In all groups BP increased compared to baseline values (p = 0.011). The decline of renal function was obvious in SHR6 (vs SHR2, p=0.001). Klotho level decreased in SHR2 vs SHR1 (p = 0.026) and in SHR4-6 vs SHR2 (p < 0.013). There were no differences in sPi (p = 0.50), PTH (p = 0.63), FGF23 (p = 0.62) between experimental groups. Perivascular myocardial fibrosis was already increased in SHR2 (vs SHR1, p=0.026, Figure 1a), renal interstitial fibrosis - since 6mo exposure (p = 0.012, Figure 2a). Both cardiac and renal fibrosis were associated with redistribution of β-catenin in cardiomyocytes and tubular epithelial cells (Figure 1a, 2a: decrease in membrane and increase in cytoplasm) without significant changes in tissue β-catenin expression. In heart β-catenin expression correlated with to perivascular fibrosis (Figure 1 b). Renal β-catenin expression correlated with interstitial fibrosis (Figure 2b), but not with sCr (r=-0.03, p>0.05) и uTP (r=0.04, p>0.05). Conclusion Reactivation of Wnt/ β-catenin signal transduction is possibly a basic molecular mechanism of cardiac and renal fibrosis in arterial hypertension. The data suggests involvement of Klotho decline mediated activation of canonical Wnt. Targeting these signaling molecules is promising therapeutic strategy for protecting both organs in cardiorenal pathology and requires further research.