Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPSUASSUNA, Paulo Giovani de AlbuquerqueCHEREM, Paula MarocoloCASTRO, Barbara Bruna deMAQUIGUSSA, EdgarCENEDEZE, Marco AntonioLOVISI, Julio Cesar MoraesCUSTODIO, Melani RibeiroSANDERS-PINHEIRO, HeladyPAULA, Rogerio Baumgratz de2020-03-242020-03-242020EXPERIMENTAL BIOLOGY AND MEDICINE, v.245, n.1, p.66-78, 20201535-3702https://observatorio.fm.usp.br/handle/OPI/35554In chronic kidney disease (CKD), evidence suggests that soluble alpha Klotho (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 alpha Klotho (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 beta-myosin heavy chain (MHC beta), alpha smooth muscle actin (alpha SMA), 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, MHC beta, and alpha SMA 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 alpha Klotho and myocardial FGF21 expression. The possibility of interaction between the alpha Klotho and FGF21 cardioprotective pathways needs to be further explored, but, if confirmed, would point to a therapeutic potential of FGF21 in uremic cardiomyopathy.engrestrictedAccessChronic kidney diseaseuremic cardiomyopathyKlothoFGF23FGF21cardiomyocyte hypertrophytrpc channelsprotectsfgf21stresshormonedeficiencyphosphatetoxicitydiseasearticleCopyright SAGE PUBLICATIONS LTD10.1177/1535370219894302Medicine, Research & Experimental1535-3699