Background: Arterial hypertension (AH) is associated with heart and chronic kidney disease (CKD). However, the precise mechanisms of myocardial remodeling (MR) in the settings of CKD remain elusive. We hypothesized that TRPC6, calcineurin/NFAT, and Wnt/β-catenin signaling pathways are involved in the development of MR in the background of CKD and AH. Methods: Early CKD was induced by performing a 5/6 nephrectomy (5/6NE) in spontaneously hypertensive rats (SHR-NE). Sham-operated (SO) SHR (SHR-SO) and Wistar Kyoto (WKY-SO) rats served as controls. Systolic blood pressure (SBP), heart rate, myocardial mass index (MMI), serum creatinine, cardiomyocyte diameter (dCM), myocardial fibrosis (MF), serum and kidney α-Klotho levels, myocardial expression of calcineurin (CaN), TRPC6, and β-catenin were measured two months after 5/6NE or SO. Results: NE-induced kidney dysfunction corresponded to mild-to-moderate human CKD and was associated with an increase in FGF23 and a decrease in renal α-Klotho. The levels of SBP, MMI, dCM, and MF were higher in SHRs compared to WKY-SO as well as in SHR-NE vs. SHR-SO. The MR was associated with increased cardiomyocyte expression of CaN/NFAT and β-catenin along with its intracellular re-distribution. TRPC6 protein levels were substantially elevated in both SHR groups with higher Trpc6 mRNA expression in SHR-NE. Conclusions: The Wnt/β-catenin and TRPC6/CaN/NFAT hypertrophic signaling pathways seem to be involved in myocardial remodeling in the settings of AH and CKD and might be mediated by FGF23 and α-Klotho axis.

INTRODUCTION.It is suggested that fibroblast growth factor 23 (FGF23) and its co-receptor Klotho are probably associatedwith changes in calcium metabolism in chronic kidney disease (CKD) due to ability to regulate intracellular Ca transport bymodulating the cationic channels TRPV5 and TRPV6.THE AIMis to investigate the association between Klotho, FGF23 and renal excretion of Ca in the initial stages of experimental CKD.MATERIAL AND METHODS.The experimental models of chronic kidney injury were resection of the renal tissue in spontaneously hypertensive rats (SHR). Serum concentrations of intact FGF23 and PTH were determined by ELISA, renal Klotho protein expression by IHC. The indices of Ca excretion were calculated.RESULTS.Serum creatinine concentration, creatinine clearance and the severity of interstitial fibrosis in experimental models corresponded to the initial stages of chronic kidney disease. UCa24 and FECa were higher, Klotho protein expression was lower in groups with more severe renal dysfunction, without significant differences in FGF23 and PTH levels. Multiple regression analysis showed that FECa and UCa24 were not associated with FGF23, Klotho, and PTH.CONCLUSION.Renal excretion of Ca in initial stages of experimental kidney damage is not associated with Klotho and FGF23 levels.

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Background. Even a moderate decrease in glomerular filtration rate leads to an increased risk of cardiovascular diseases (CVD), which is the leading cause of mortality in patients with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) underlies CVD development in renal dysfunction. The prevalence of LVH in patients with CKD stages 2–4 is 50–70 % and reaches 95 % at the beginning of dialysis, which significantly exceeds the number of cases in general population (15–21 %). Common hemodynamic factors associated with chronic kidney damage —hypertension (HTN), activation of the renin-angiotensin system, anemia, fluid and sodium retention, and others largely explain the high prevalence of LVH among patients with CKD. Nevertheless, the existence of additional non-hemodynamic mechanisms of myocardial remodeling (MR) is evident.Objective. To investigate the associations between the MR physiological/histological characteristics and laboratory parameters of calcium-phosphate metabolism in the initial stages of experimental CKD. Design and methods. Four groups of spontaneously hypertensive rats (SHR) were studied (n = 35): 3/4 nephrectomized rats (Nx) one month exposed after surgery (Nx(1), n = 9), 5/6 Nx two months after surgery (Nx(2), n = 8), sham operated rats one month after surgery (SO(1), n = 9) and two months after surgery (SO(2), n = 9). Myocardial mass index (MMI), systolic blood pressure (BP), proteinuria, creatinine (Cr) concentration, total calcium (Ca) and inorganic phosphate (Pi), 25-OH vitamin D (25OHD) and parathyroid hormone (PTH) in serum, myocardial morphology were studied in all experimental animals.Results. The models corresponded to the 1–3 stages CKD. There were no significant changes in serum total Ca (p = 0,066), Pi (p = 0,051) and PTH (p = 0,015) concentrations, the level of 25OHD was significantly lower in Nx(2) rats vs control (p = 0,015). MMI increased in all nephrectomized rats (p = 0,008). The cardiomyocytes (CM) thickness increased in Nx(1) and Nx(2) animals compared to the corresponding controls (p = 0,010, p = 0,002). A significant increase in interstitial (IF) and perivascular (PF) fibrosis occurred in Nx(2) rats with more damaging influence (p = 0,017, p = 0,004). CM thickness, IF and PF increased with the elevation of BP (r = 0,39, p = 0,038, r = 0,47, p = 0,026, r = 0,49, p = 0,031) and serum Cr (r = 0,68, p = 0,001, r = 0,61, p = 0,003, r = 0,69, p = 0,001), and the decrease in serum 25OHD concentration (r = –0,045, p = 0,047, r = –0,50, p = 0,020, r = –0,52, p = 0,012). Multiple linear regression analysis showed, that 25OHD is an independent predictor of myocardial fibrosis (IF: β = –0,38 ± 0,18, p = 0,047, PF: β = –0,34 ± 0,15, p = 0,032).Conclusions. The initial stages of CKD accompanied with HTN are associated with serum 25OHD concentration decrease CM hypertrophy and myocardial fibrosis. The CM growth is an earlier event in relation to the interstitial fibrosis. The obtained data suggest a possible role of vitamin D deficiency in the development of myocardial fibrotic lesions.

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.