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

Abstract

Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.

Emerging Biomarkers for Predicting Clinical Outcomes in Patients with Heart Disease

“…In order to exert its renal effects and contribute to the development of the cardiorenal syndrome, FGF-23 needs to bind to certain receptors in the presence of a co-factor called Klotho, promoting phosphaturia. FGF-23 may also have direct effects on the heart, in a Klotho-independent interaction [ 74 ]. Experimental studies suggested that, in the heart, FGF-23 may contribute to myocardial hypertrophy, endothelial dysfunction and atherosclerosis, and, therefore, may be used as a biomarker of CV disease [ 73 ].…”

Partial Genetic Deletion of Klotho Aggravates Cardiac Calcium Mishandling in Acute Kidney Injury

“…Alterations in mineral metabolism, including those involving klotho deficiency and increased circulating FGF23 levels, have been linked to kidney disease. However, they may also have direct cardiovascular effects in patients in the different stages of CKD and AKI [ 10 ]. At an experimental level, it has been recently described that ventricular adult cardiomyocytes show relevant functional damage in the first hours after AKI where kidney klotho expression drops significantly [ 20 ].…”

“…It has been demonstrated that serum levels of klotho decrease with aging and it is also associated with several typical age-related disorders such as diabetes, vascular calcification, atherosclerosis, cardiovascular and renal diseases [ 4 , 6 , 9 ]. In the kidney, low circulating plasma soluble klotho levels have been correlated with worsening renal function in chronic kidney disease (CKD) and end-stage renal disease (ESRD) as well as in acute kidney injury (AKI) [ 10 ]. Furthermore, low soluble klotho levels are associated with arterial stiffness in CKD, increased cardiovascular mortality rate in haemodialysis and cardiovascular disease risk factors in older adults [ 11 , 12 , 13 ].…”

Pharmacological and Genetic Inhibition of HDAC4 Alleviates Renal Injury and Fibrosis in Mice

“…As such, HDAC4 may be a critical mediator in regulating the depression of Klotho during the acute phase and perhaps chronic phase of renal injury following UUO. Since Klotho functions as a coreceptor of FGF receptors (FGFRs) to activate a specific fibroblast growth factor 23 (FGF23) signal pathway and FGF23 exerts its biological effects in a Klotho-dependent manner ( Lu and Hu, 2017 ; Navarro-Garcia et al, 2021 ), it is possible that HDAC4-mediated regulation of Klotho may also indirectly influence the biological functions of FGF23 such as mineral homeostasis and CKD-related bone disorders and cardiovascular problems. Furthermore, an investigation is needed to address these issues.…”