Myocardial Hypertrophy and Fibrosis Are Associated with Cardiomyocyte Beta-Catenin and TRPC6/Calcineurin/NFAT Signaling in Spontaneously Hypertensive Rats with 5/6 Nephrectomy

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.

Keywords

• arterial hypertension
• cardiac remodeling
• chronic kidney disease
• calcineurin A
• calcineurin B
• NFAT