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.

KYA1797K, a Novel Small Molecule Destabilizing β-Catenin, Is Superior to ICG-001 in Protecting against Kidney Aging

“…Although we could not prove that in the present study, our results at least show that TCF/LEF-1 pathway is not the only downstream effector, since ICG-001 did not exhibit the same efficacy as KYA1797K. Since Wnt/β-catenin signaling has been involved in the pathogenesis of a variety of tissue fibrosis [42][43][44][45][46][47], we believe that KYA1797K, which could induce the destabilization of β-catenin, may also have beneficial effects on these fibrotic disorders.…”

The SOCE Machinery: An Unbalanced Knowledge between Left and Right Ventricular Pathophysiology

“…Almost all TRPC isoforms are differentially expressed in left ventricular tissue and cells isolated from experimental animal models of LV remodeling and dysfunction, and in myocardial biopsies from failing human hearts ( Table 1 and Figure 1 ). Indeed, in different in vivo experimental rodent models of hypertrophy and HF induced by pressure or volume overload (abdominal, ascending or transverse aortic constriction, Dahl salt-sensitive, spontaneously hypertensive (SHR), myocardial infraction, ischemia-reperfusion injury) or by neurohormonal stress (PE, Endothelin-1 (ET-1), AngII, Isoproterenol), an increased expression of TRPC1 [ 54 , 57 , 59 , 65 , 82 , 88 , 89 , 90 , 91 , 92 ], TRPC2 [ 90 ], TRPC3 [ 59 , 90 , 93 , 94 , 95 , 96 ], TRPC4 [ 59 , 81 , 97 ], TRPC5 [ 83 ] and TRPC6 [ 59 , 72 , 81 , 90 , 94 , 95 , 96 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ] has been reported. Additionally, increased TRPC1 and TRPC5 expression in failing human hearts [ 93 , 105 , 106 ], increased TRPC6 mRNA in human LV with dilated cardiomyopathy [ 100 ], and decreased expression of TRPC4 in isolated LV myocytes from patients with ischemic cardiomyopathy and severe HF have been shown [ 105 , 107 ] (…”

Exosomes and Exosomal Cargos: A Promising World for Ventricular Remodeling Following Myocardial Infarction

“… 4 , 5 Recent studies have revealed that TRPC6/Calcineurin/NFAT and cWnt/β-catenin signaling pathways are associated with pathological hypertrophy. 6–8 Jia et al reported that Bcl2-associated athanogene 3 (BAG3) promotes physiological hypertrophy by activating the Akt/mTOR pathway while attenuating pathological hypertrophy by inhibiting the TRPC6/CaN/NFAT pathway. 9 Although a beneficial adaptive response initially, myocardial hypertrophy transforms into a detrimental change and progresses into HF eventually under persistent pathological stimuli.…”