Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Apr 28;22(9):4645.
doi: 10.3390/ijms22094645.

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

Evdokia Bogdanova  1 , Olga Beresneva  1 , Olga Galkina  1 , Irina Zubina  1 , Galina Ivanova  2 , Marina Parastaeva  1 , Natalia Semenova  3   4 , Vladimir Dobronravov  1
Affiliations

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

Evdokia Bogdanova et al. Int J Mol Sci. .

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: Klotho; NFAT; TRPC6; arterial hypertension; calcineurin A; calcineurin B; cardiac remodeling; chronic kidney disease; fibroblast growth factor 23; parathyroid hormone; β-catenin.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kidney function and myocardial remodeling in the model of hypertension and chronic renal dysfunction (SHR-NE) and controls (SHR-SO, WKY-SO): (a) serum creatinine, (b) blood pressure, (c) myocardial mass index, (d) cardiomyocyte diameter (H&E and quantitative morphometry), (e) interstitial fibrosis (Masson’s staining and quantitative morphometry), and (f) Tgfβ1 mRNA relative expression; WKY—Wistar Kyoto rats; SHR—spontaneously hypertensive rats; SO—sham-operated; and NE—nephrectomy.
Figure 2
Figure 2
Myocardial expression of β-catenin (IHC): (a) representative microphotographs of myocardial β-catenin IHC staining in WKY-SO, SHR-SO, and SHR-NE groups (white arrows—the cytoplasmic expression; grey arrows—intercalated discs; black arrows—the nuclear expression; scale bar, 50 um); (b) the total area of myocardial β-catenin expression; WKY—Wistar Kyoto rats; SHR—spontaneously hypertensive rats; SO—sham-operated; NE—nephrectomy; FOV—field of view.
Figure 3
Figure 3
Myocardial expression of calcineurin/NFAT and TRPC6: (a) the representative microphotographs of the myocardial expression of TRPC6/CaN/NFAT; the morphometric analysis of myocardial (b) TRPC6 (200×; scale bar, 100 μm), (c) CaN (200×), and (d) nuclear NFATc3 (400×; scale bar, 50 μm) IHC staining; and (c) the relative mRNA expression of (e) Trpc6, (f) calcineurin A (Ppp3ca) and (g) calcineurin B (Ppp3r1) in controls, hypertension, and renal dysfunction; FOV—field of view; Nu—nuclei.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Maillet M., van Berlo J.H., Molkentin J.D. Molecular basis of physiological heart growth: Fundamental concepts and new players. Nat. Rev. Mol. Cell Biol. 2013;14:38–48. doi: 10.1038/nrm3495. - DOI - PMC - PubMed
    1. Hayashi K., Suzuki T., Sakamaki Y., Ito S. Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23. Ren. Replace. Ther. 2018;4:10. doi: 10.1186/s41100-018-0152-0. - DOI
    1. Yu W., Chen C., Cheng J. The role and molecular mechanism of FoxO1 in mediating cardiac hypertrophy. ESC Heart Fail. 2020;22:3497–3504. doi: 10.1002/ehf2.13065. - DOI - PMC - PubMed
    1. Bers D.M. Cardiac excitation-contraction coupling. Nature. 2002;415:198–205. doi: 10.1038/415198a. - DOI - PubMed
    1. Freichel M., Schweig U., Stauffenberger S., Freise D., Schorb W., Flockerzi V. Store-operated cation channels in the heart and cells of the cardiovascular system. Cell. Physiol. Biochem. 1999;9:270–283. doi: 10.1159/000016321. - DOI - PubMed

LinkOut - more resources