Abstract
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.
Highlights
The systolic blood pressure (SBP) and serum creatinine were expectedly higher in spontaneously hypertensive rats (SHR) with 5/6 nephrectomy (SHR-NE) compared to shamoperated SHR (SHR-SO) and sham-operated Wistar Kyoto rats (WKY-SO) (Figure 1a,c)
The increase in myocardial mass index (MMI), diameter of cardiomyocytes, and area of myocardial interstitial fibrosis (IF) were obvious in both SHR groups compared to WKY-SO
Calcineurin; NFAT—nuclear factor of activated T-cells; FOV—field of view, * p < 0.05. This proof-of-concept study clearly demonstrated the contribution of chronic kidney disease (CKD) to pathological myocardial remodeling in the background of Arterial hypertension (AH). The latter fact concerned the severity of cardiomyocyte hypertrophy and interstitial fibrosis, which was in turn was associated with the up-regulation of the studied signaling pathways: β-catenin, transient receptor potential channels (TRPC)/CaN/NFAT, and the imbalance in α-Klotho/fibroblast growth factor 23 (FGF23) axis
Summary
Myocardial remodeling (MR) including cardiomyocyte hypertrophy and interstitial fibrosis is a multifactorial process that develops in response to various pathological stimuli such as pressure overload, neuroendocrine activation, production of paracrine and autocrine factors, as well as impaired energy metabolism [1,2,3]. TRPCs are activated by neuroendocrine factors (catecholamines, angiotensin II) and are involved in the development of arrhythmias, fibrosis and myocardial hypertrophy [5]. Overexpression of canonical TRPCs promotes a rapid increase in the concentration of intracellular Ca2+ and the activation of one of the main prohypertrophic pathways—the calcium and calmodulin-dependent calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling [6,7,8]. 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
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