Chronic kidney disease (CKD), impacting around 8 to 15 percent of the global population, is distinguished by a progressive deterioration in renal function and is on the rise in terms of both occurrence and prevalence [1]. In 2040, CKD will account for the fifth-highest rate of death [2]. CKD patients die primarily from cardiovascular disease (CVD). Nearly half of individuals with stage 4-5 CKD also have CVD. Compared to those with normal kidney function, deaths from CVD account for 40–50% of all deaths among patients with stages 4–5 of CKD [3].
Traditional risk factors for CVD encompass older age, male gender, hypertension, hyperlipidemia, diabetes, and smoking, all of which are prevalent in CKD patients. These conventional risk factors seem to be the primary etiological elements for CVD in individuals with mild-to-moderate CKD [4]. Non-CKD-specific risk factors can also significantly contribute to CVD, primarily through vascular calcification (VC) and valvular complications in patients with advanced CKD [5]. Hydroxyapatite is a major manifestation of VC, where calcium and phosphorus metabolism disorders cause abnormal calcium phosphate crystal deposits on the blood vessel wall. The presence of VC is thought to be a reliable predictor of vascular morbidity and mortality in CKD, which can manifest as coronary artery disease, angina, heart failure, or sudden cardiac death [6-7]. To date, there is no effective treatment strategy to prevent or treat VC.
The pathological mechanism of VC mainly involves the transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast cells stimulated by a variety of factors, the apoptosis of VSMCs and the release of matrix vesicles, resulting in the increased expression of bone-associated proteins (e.g., Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN)) and decreased expression of VSMCs-specific marker proteins (eg, α-smooth muscle actin [α-SMA]) [8]. Studies have confirmed that aldosterone can exert procalcification effects by promoting oxidative stress, inflammation, and apoptosis, and is a significant VC pathogen [9]. On one hand, aldosterone has the ability to bind to the mineralocorticoid receptor (MR) and control the transcription of downstream target genes. These genes are subsequently translated into various aldosterone-inducible proteins, which include markers related to VC, which include alkaline phosphatase (ALP) and bone morphogenetic protein 2 (BMP-2). On the other hand, aldosterone can amplify non-genomic reactions by activating second messengers and protein kinases through membrane receptors [10]. However, research on the promotion of VC by aldosterone is still very limited, and the underlying mechanism is unclear.
Calcium-binding allograft inflammation factor-1 (AIF-1) encoded by genomic region 1 of HLA class III is a protein with an EF chiral structure, first identified in human-activated macrophages and allogeneic heart transplant rats [11]. Researchers have reported that AIF-1 increases cardiovascular risk and that when VSMCs specifically overexpress AIF-1, atherosclerosis increases, and conversely, knockdown of AIF-1 attenuates intimal hyperplasia caused by guidewire injury to the carotid artery in rats [12-13]. In addition, AIF-1 can also increase osteogenic transdifferentiation of VSMCs [14]. In prior experiments, aldosterone has been shown to promote apoptosis and calcification of VSMCs through the AIF-1/NF-κB signaling pathway [15].
Wnt proteins are a wide-range of family of secretory signaling molecules that bind to the coreceptor complex made up of low-density lipoprotein-receptor-related proteins 5 and 6 (LPR5/6) and the transmembrane receptor (FZD). β-catenin translocates into the nucleus during activation of the canonical Wnt signaling pathway, which also controls the expression of downstream target genes [16]. The Wnt/β-catenin signaling pathway mediates the occurrence and progression of a variety of diseases, especially in skeletal development [17]. It has been demonstrated that the Wnt/β-catenin signaling pathway controls the phosphorus-induced osteogenic transdifferentiation and calcification of VSMCs [18-19]. In addition, adenosine-induced rat models of CKD have furthermore shown that the application of aldosterone receptor antagonists can attenuate vascular calcification while inhibiting the activation of the Wnt/β-catenin pathway, suggesting that hyperaldosteronism promotes the progression of vascular calcification by upregulating the Wnt/β-catenin pathway in rats with CKD [20].
The main hallmark of CKD is a persistent microinflammatory state in vivo, which contributes to VC development [28-29]. In most patients with CKD, there is an increase in aldosterone levels, which induces oxidative stress and inflammatory response, and under the stimulation of inflammatory factors, on the one hand, VSMCs can rapidly express AIF-1 and promote cell migration and phenotypic transdifferentiation, and on the other hand, by activating the Wnt/β-catenin signaling pathway, it promotes VSMC osteogenic transdifferentiation; however, its interaction with Wnt/β-catenin is still unknown.
As part of our investigation, we concentrated on the potential functions and mechanisms through which aldosterone can instigate vascular calcification. We also examined the interaction between aldosterone and AIF-1 and Wnt/β-catenin signaling pathways, aiming to offer novel perspectives on the pathogenesis of VC in CKD and identify new therapeutic targets for its management.