Introduction. Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD), which is termed cardiorenal syndrome type 4 (CRS-4). Here, we report the development of pathological cardiac remodeling and fibrosis in unilateral urinary obstruction (UUO) rats. Methods. Hematoxylin and eosin (HE) staining was performed to observe the pathology of myocardial tissue. The degree of myocardial tissue fibrosis was observed by Masson and Sirius red staining. Immunohistochemical staining was applied to detect the expression of CD34 and CD105 in myocardial tissue, and immunofluorescent staining was performed to examine the expression of CD34, collagen I/collagen III, and alpha smooth muscle actin (α-SMA). The expression of the signal pathway-related proteins vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), nuclear factor κB (NF-κB), and interleukin (IL)-1β was tested by western blotting. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the mRNA levels of serum and glucocorticoid-inducible kinase (SGK)-1, NF-κB, and interleukin-1β (IL-1β). Results. The results showed the development of pathological cardiac remodeling and cardiac dysfunction in UUO rats. Moreover, there was more angiogenesis and endothelial-mesenchymal transition (End-MT) in the UUO group, and these effects were inhibited by eplerenone. Conclusions. The results indicated that this cardiac fibrosis was associated with angiogenesis and that End-MT was related to aldosterone and mineralocorticoid receptor (MR) activation. Moreover, in association with the MR/IL-1β/VEGFA signaling pathway, early treatment with the MR antagonist eplerenone in rats with UUO-induced CKD may significantly attenuate MR activation and cardiac fibrosis.

Renal fibrosis is an inevitable process in the progression of chronic kidney disease (CKD). Angiogenesis plays an important role in this process. Vascular endothelial cells are involved in renal fibrosis by phenotypic transformation and secretion of extracellular matrix. Aldosterone stimulates mineralocorticoid receptor (MR) activation and induces inflammation, which is important for angiogenesis. Clinically, MR blockers (MRBs) have a protective effect on damaged kidneys, which may be associated with inhibition of angiogenesis. In this study, we used aldosterone-infused mice and found that aldosterone induced angiogenesis and that endothelial-mesenchymal transition (EndMT) in neovascular endothelial cells was involved in renal fibrosis. Notably, aldosterone induced inflammation and stimulated macrophages to secrete vascular endothelial growth factor (VEGF) A to regulate angiogenesis by activating MR, whereas EndMT occurred in response to transforming growth factor-β1 (TGF-β1) induction and participated in renal fibrosis. These effects were antagonized by the MRB esaxerenone. These findings suggest that reducing angiogenesis may be an effective strategy for treating renal fibrosis.

Vascular smooth muscle cells (VSMCs) are the most abundant cell type in blood vessels, participating in cardiovascular diseases in various ways, among which their transformation into macrophage-like cells has become a research hotspot. In this study, rats were infused with aldosterone for 12 weeks, and VSMCs stimulated with aldosterone in vitro were used to observe aortic injury and the role of VSMC transformation. Vascular changes were detected via small animal ultrasound and H&E staining. Moreover, immunohistochemistry, immunofluorescence, Western blot, and flow cytometry were used to verify that the transformation of VSMCs into macrophage-like cells is regulated by mineralocorticoid receptor (MR) activation and macrophage colony-stimulating factor (M-CSF) and its receptor. Rat vasculature and in vitro cellular experiments revealed that VSMCs transformed into macrophage-like cells and secreted inflammatory factors such as interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), thereby exacerbating inflammatory vascular lesions, which was inhibited by the MR antagonist esaxerenone. These results reveal that increased levels of aldosterone activate MR, leading to the secretion of M-CSF by VSMCs. This further promotes the transformation of VSMCs into macrophage-like cells, which participate in inflammatory vascular lesions. Therefore, inhibiting the formation of macrophage-like cells can effectively reduce inflammatory vascular lesions.

Chronic kidney disease (CKD) involves progressive and irreversible loss of renal function, often causing complications and comorbidities and impairing the function of various organs. In particular, lung injury is observed not only in advanced CKD but also in early‑stage CKD. The present study investigated the potential involvement of mineralocorticoid receptors (MRs) and lymphatic vessels in lung injury using a 180‑day unilateral ureteral obstruction (UUO) model for CKD. Changes in lung associated with lymphangiogenesis and inflammatory were analyzed in UUO rats. The pathology of the lung tissue was observed by hematoxylin and eosin and Masson's staining. Detection of the expression of lymphatic vessel endothelial hyaluronic acid receptor‑1 (LYVE‑1), Podoplanin, vascular endothelial growth factor receptor‑3 (VEGFR‑3) and VEGF C to investigate lymphangiogenesis. The mRNA and protein expression levels of IL‑1β, monocyte chemotactic protein 1, tumor necrosis factor‑α, nuclear factor κB, phosphorylated serum and glucocorticoid‑induced protein kinase‑1 and MR were evaluated using western blot, reverse transcription‑quantitative PCR, immunohistochemical staining and immunofluorescence staining. In the present study, long‑term UUO caused kidney damage, which also led to lung inflammation, accompanied by lymphangiogenesis. However, treatment with eplerenone, an MR blocker, significantly reduced the severity of lung injury and lymphangiogenesis. Therefore, lymphangiogenesis contributed to lung fibrosis in UUO rats due to activation of MRs. In addition, transdifferentiation of lymphatic epithelial cells into myofibroblasts may also be involved in lung fibrosis. Collectively, these findings provided a potential mechanism for lung fibrosis in CKD and suggested that the use of eplerenone decreased kidney damage and lung fibrosis.