αKlotho attenuates cardiac hypertrophy and increases myocardial fibroblast growth factor 21 expression in uremic rats

Abstract

In chronic kidney disease (CKD), evidence suggests that soluble αKlotho (sKlotho) has cardioprotective effects. Contrariwise, high circulating levels of fibroblast growth factor 23 (FGF23) are related to uremic cardiomyopathy development. Recently, it has been demonstrated that sKlotho can act as a soluble FGF23 co-receptor, allowing sKlotho to modulate FGF23 actions in the myocardium, leading to the activation of cardioprotective pathways. Fibroblast growth factor 21 (FGF21) is a cardiomyokine with sKlotho-like protective actions and has never been evaluated in uremic cardiomyopathy. Here, we aimed to evaluate whether recombinant αKlotho (rKlotho) replacement can attenuate cardiac remodeling in an established uremic cardiomyopathy, and to explore its impact on myocardial FGF21 expression. Forty-six male Wistar rats were divided into three groups: control, CKD-untreated, and CKD treated with rKlotho (CKD + KL). CKD was induced by 5/6 nephrectomy. From weeks 4–8, the control and CKD-untreated groups received vehicle, whereas the CKD + KL group received subcutaneous rKlotho replacement (0.01 mg/kg) every 48 h. Myocardial remodeling was evaluated by heart weight/tibia length (HW/TL) ratio, echocardiographic parameters, myocardial histomorphometry, and myocardial expression of β-myosin heavy chain (MHCβ), alpha smooth muscle actin (αSMA), transient receptor potential cation channel 6 (TRPC6), and FGF21. As expected, CKD animals had reduced levels of sKlotho and increased serum FGF23 levels. Compared to the control group, manifest myocardial remodeling was present in the CKD-untreated group, while it was attenuated in the CKD + KL group. Furthermore, cardiomyocyte diameter and interstitial fibrotic area were reduced in the CKD + KL group compared to the CKD-untreated group. Similarly, rKlotho replacement was associated with reduced myocardial expression of TRPC6, MHCβ, and αSMA and a higher expression of FGF21. rKlotho showed cardioprotective effects by attenuating myocardial remodeling and reducing TRPC6 expression. Interestingly, rKlotho replacement was also associated with increased myocardial FGF21 expression, suggesting that an interaction between the two cardioprotective pathways needs to be further explored. Impact statement This study aimed to evaluate whether rKlotho replacement can attenuate cardiac remodeling in a post-disease onset therapeutic reasoning and explore the impact on myocardial FGF21 expression. This study contributes significantly to the literature, as the therapeutic effects of rKlotho replacement and FGF21 myocardial expression have not been widely evaluated in a setting of uremic cardiomyopathy. For the first time, it has been demonstrated that subcutaneous rKlotho replacement may attenuate cardiac remodeling in established uremic cardiomyopathy and increase myocardial expression of FGF21, suggesting a correlation between αKlotho and myocardial FGF21 expression. The possibility of interaction between the αKlotho and FGF21 cardioprotective pathways needs to be further explored, but, if confirmed, would point to a therapeutic potential of FGF21 in uremic cardiomyopathy.

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

“…The mechanisms of MR in CKD are poorly understood and may include hemodynamic and non-hemodynamic factors [ 26 , 27 , 28 , 29 , 30 , 31 ]. The increased production of fibroblast growth factor-23 [ 32 , 33 ], αKlotho [ 34 , 35 ], and calcitriol [ 36 ] deficiencies are major candidate non-hemodynamic factors of cardiomyopathy progression in patients with CKD [ 37 , 38 , 39 , 40 ].…”

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets

“…Several experimental studies have demonstrated that sKL treatment prevents heart alterations found following renal dysfunction. Thus, sKL treatment was found to prevent FGF-23-induced cardiac hypertrophy ( Han et al, 2020 ; Suassuna et al, 2020 ) and dysfunction ( Navarro-García et al, 2020 ) in experimental CKD models. In this line, Klotho overexpression has been shown to prevent cardiac alterations in a uremic milieu ( Navarro-García et al, 2020 ).…”

Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Chronic Kidney Disease—A Pediatric Perspective

“…However, clinical studies on the therapeutic benefit of anti-FGFR4 antibodies in LVH are still pending. Treatment of uremic cardiomyopathy in rodents with recombinant αKlotho ameliorated LVH and fibrosis independent of high FGF23 synthesis ( Figure 3 ), but again, clinical studies are lacking to prove the positive effects of Klotho therapy on the CV system ( 121 ).…”