No 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.

Objective. To investigate the proliferation effect of aldosterone on renal tubular epithelial cells in vivo and in vitro. Methods. Thirty-two male C57BL/6J mice (20–22 g) were divided randomly into four groups: sham, unilateral nephrectomy (UN), unilateral nephrectomy plus aldosterone infusion (UA), and UA plus eplerenone (UAE). The kidneys were removed 6 weeks after treatment. Expression of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry and western blotting. Human kidney proximal tubular epithelial (HK2) and mouse distal convoluted tubule (mDCT) cell lines were stimulated by aldosterone (0, 10−9, 10−8, 10−7, and 10−6 mol/L) in vitro. Cells were collected after 3, 6, 12, 24, 36, and 48 h, and proliferation of each group detected by western blotting, flow cytometry, live imaging, and the MTT assay. In addition, mDCT cells were costimulated with a medium containing a final concentration of 161 mmol/L Na+ and different concentrations of aldosterone, and the number of cells and cellular DNA content was measured by the MTT assay and flow cytometry. Results. Aldosterone could induce a significant increase in the number of PCNA-positive cells in mouse kidneys accompanied by increased deposition of collagen fibers. Eplerenone could inhibit aldosterone-induced cell proliferation and collagen deposition. HK2 cells and mDCT cells administered different concentrations, and different times of aldosterone stimulation failed to cause cell proliferation, and costimulation of aldosterone and salt did not cause proliferation changes in mDCT cells. Conclusions. Aldosterone perfusion can induce proliferation of mouse kidney cells in vivo, and eplerenone can inhibit this change, but aldosterone stimulates HK2 cells and mDCT in vitro without causing their proliferation.