Eplerenone ameliorates lung fibrosis in unilateral ureteral obstruction rats by inhibiting lymphangiogenesis

Abstract

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.

A combination of 5/6‐nephrectomy and unilateral ureteral obstruction model accelerates progression of remote organ fibrosis in chronic kidney disease

“…However, the protein expression of type 1 collagen did not change in the lungs within 1 month. The kidneys and lungs are closely linked in CKD pathology; however, lung fibrosis may take a long time to develop 16,37 …”

“…The kidneys and lungs are closely linked in CKD pathology; however, lung fibrosis may take a long time to develop. 16 , 37 …”

“…The kidneys and lungs are closely linked in CKD pathology; however, lung fibrosis may take a long time to develop. 16,37 In this study, we investigated the development of remote organ fibrosis using classical CKD models, such as UUO, 5/6 Nx, and their combinations. The 5/6 Nx model is generated by surgical removal of renal tissue, which leads to a decrease in the absolute number of nephrons and causes loss of renal function.…”

Angiogenesis—An Emerging Role in Organ Fibrosis

“…In addition, LEC transdifferentiation into myofibroblasts is also the cause of lymphangiogenesis to promote fibrosis. In a rat lung and heart fibrosis model, lymphatic endothelial cells were observed to coexpress α-SMA and β, namely, new lymphatic endothelial cells can transdifferentiate into myofibroblasts or undergo the endothelial mesenchymal transition process, and a large deposition of collagen I was observed around the lymphatic vessels [ 87 , 90 ]. Myofibroblasts are considered central factors during tissue healing and tissue fibrosis.…”