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.

Изменения экспрессии микроРНК в моче яванских макак (Macaca fascicularis) при высоком потреблении поваренной соли

Doxorubicin is widely used as an antitumor drug, but it has a negative effect on the cardiovascular system. While special attention has mainly been paid to its cardiotoxic effect, the mechanisms of its action on vessels are not well understood. In this in vivo study, we assessed the vascular reactivity of rat mesenteric arteries to vasoactive agents and the involvement of mechanisms of endothelium-dependent vasodilation in rats treated with a single dose of doxorubicin. Experimental Wistar rats received a single intraperitoneal injection of doxorubicin (4 mg/kg), while control animals were i.p. injected with a physiological saline in the same volume. After 6 weeks, the reactivity of mesenteric arteries to acetylcholine (ACh), sodium nitroprusside, and phenylephrine was examined. To elucidate the mechanisms of endothelium-dependent vasodilation, the following blockers were used: L-NAME for endothelial NO synthase, indomethacin for cyclooxygenase, tetraethylammonium for large-conductance Ca²⁺-activated K⁺ channels. To assess arterial reactivity in vivo, microphotographic and video records of the diameter of mesenteric arteries were obtained using a Biomed MC-1T-ZOOM microscope with a Basler acA4600-10uc camera and processed using the MultiMedia Catalog software. Doxorubicin modified the reactivity of rat mesenteric arteries of rats, increasing their phenylephrine-induced vasoconstriction and inhibiting ACh-induced endothelium-dependent vasodilation. At the same time, doxorubicin administration led to a decrease in the efficiency of NO-dependent mechanisms of vascular tone regulation, as assessed by the difference in the amplitude of ACh-induced vasodilation before and after L-NAME application, as well as to a decrease in the sodium nitroprusside-induced arterial relaxation, as compared to control animals. Doxorubicin had no effect on the efficiency of prostaglandin-, small- and intermediate-conductance Ca²⁺-activated K⁺ channel-mediated mechanisms of endothelium-dependent vasodilation.

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.

A high salt diet leads to a decrease in vascular dilatation to agonists, but the vascular mechanisms involved in this process are not extensively studied. A group of male Wistar rats at the age of 3 months was transferred to a high-salt diet containing 8% NaCl (HS) for 3 months, while the second group received a normal-salt diet with a standard salt content (0.34%) (NS). At the end of the experiment, the rats were euthanized and the abdominal aorta and superior mesenteric artery (SMA) were extracted. The vascular segments were placed into a myograph, and the acetylcholine (ACh)-induced relaxation of the phenylephrine (PHE)-precontracted vascular segments was measured. A high-salt diet led to attenuate the relaxation of the SMA in a calcium-free solution. In response to ACh and sodium nitroprusside, a pronounced relaxation of the vascular segments was observed, while the ACh-induced vascular relaxation in HS rats showed a lower amplitude. Potassium channel blockers (TEA, TRAM-34, apamine) attenuated the ACh-induced relaxation of the SMA, but not the aorta. In the SMA of HS rats, a decrease in the relaxation under the effect of K⁺ channel blockers was more prominent. Inhibition of the production of endogenous hydrogen sulfide (H₂S) also led to attenuate the ACh-induced relaxation of SMA segments. In SMA of HS rats, the degree of attenuation of the ACh-induced relaxation against the background of propargylglycine was larger than in NS rats. The data obtained in the study show that a long-term high-salt diet leads to a decrease in agonist-induced relaxation of the aortic segments and SMA due to a decrease in the production of NO by the endothelium. In the SMA of HS rats, a decrease in NO-mediated relaxation is partially compensated by the increasing role of EDHF in ACh-induced relaxation. The results of the study also show that one of the EDHFs in the rat SMA is H₂S, the role of which in SMA relaxation increases in HS rats.