eplerenone and Ureteral-Obstruction

Cardiorenal syndrome (CRS) is the leading cause of death associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, the underlying mechanisms of CRS are still poorly understood. Here, we studied a CKD model of unilateral ureteral obstruction (UUO) and observed pathological cardiac fibrosis and lymphangiogenesis in 180-day old UUO rats, in which inflammatory injury plays a major role. In addition, treatment of UUO rats with eplerenone, a mineralocorticoid receptor blocker (MRB), significantly reduced cardiac lymphangiogenesis and fibrosis. In conclusion, our experimental results showed that cardiac lymphangiogenesis in long-term UUO rats may be involved in the formation of cardiac fibrosis and that eplerenone can alleviate lymphangiogenesis and cardiac fibrosis by inhibiting inflammation.

Topics: Animals; Disease Models, Animal; Eplerenone; Fibrosis; Kidney; Lymphangiogenesis; Rats; Renal Insufficiency, Chronic; Ureteral Obstruction

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.. Hematoxylin and eosin (H&E) 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 (. 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.

Topics: Actins; Aldosterone; Animals; Collagen; Eosine Yellowish-(YS); Eplerenone; Fibrosis; Glucocorticoids; Hematoxylin; Interleukin-1beta; Kidney; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; RNA, Messenger; Ureteral Obstruction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Ventricular Remodeling

Yiqi Huoxue Tongluo recipe (YHTR) is a traditional Chinese medicine for the treatment of chronic kidney disease, but its exact mechanism is not clear.. To monitor the potential improvement of renal mitochondrial function in unilateral ureteral obstruction (UUO) rats by regulating NR4A1 using the YHTR.. Wistar rats were randomly divided into four groups: sham, UUO (left ureteral ligation for 14 days), eplerenone (EPL) (UUO + EPL), and YHTR (UUO + YHTR). UUO rats were established and intragastrically administered EPL (100 mg/day/kg) or YHTR (11.7 g/day/kg) for 14 days. The expression of related proteins in kidneys was detected by immunohistochemistry, western blot, RT-PCR, and chemical colorimetric assay, respectively.. YHTR significantly improved the development of CKD; this study may provide new ideas for the pathogenesis of CKD and new strategies for the development of new drugs against CKD.

Topics: Animals; Eplerenone; Mitochondria; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Ureteral Obstruction

Progression of chronic kidney disease (CKD) to uremia is often accompanied by varying degrees of lung damage and this is also an important cause of death. Although there are many studies on the mechanism of lung injury, it is not clearly understood. Inflammatory macrophages may associated with fibrosis in the lungs. Here, we investigated the role of macrophage-myofibroblast transition (MMT) in lung fibrosis with unilateral ureteral obstruction (UUO) rats. We found that cells undergoing MMT accounted for an important part of the myofibroblast population, and correlated with lung fibrosis, MMT cells in lungs have a predominant M2 phenotype, and this process was attenuated after treatment with eplerenone. In conclusion, our studies provide a possible mechanism for UUO-induced kidney damage and lung injury, indicating the possibility of using eplerenone, a mineralocorticoid receptor blocker, to treat UUO to reduce kidney damage and protect lung function.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Eplerenone; Humans; Macrophages; Male; Mineralocorticoid Receptor Antagonists; Myofibroblasts; Protective Agents; Pulmonary Fibrosis; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Ureteral Obstruction

The progression of chronic renal failure in patients with unilateral renal injury is associated with loss of function in the contralateral kidney, but the molecular mechanism remains unclear. The activation of mineralocorticoid receptor (MR) in the kidney contributes to renal cell damage, leading to apoptosis, pyroptosis, and necrosis. Pyroptosis is a programmed cell death induced by caspase-1, which is usually activated by nod-like receptor pyrin-containing 3 (NLRP3) inflammasomes. Our study aimed to investigate the effects of eplerenone (EPL) on cell pyroptosis in the contralateral kidneys of unilateral ureteral obstruction (UUO) rats.. Sprague-Dawley rats were randomly divided into 3 groups: sham group, UUO group (10 days of left ureter ligation), and UUO treated with EPL (UUO + EPL) group. The contralateral kidneys of all rats were collected for studies.. We observed evidently increased number of pyroptosis cells in the contralateral kidneys of UUO rats compared to those from Sham rats. The expression of NLRP3, caspase-1, interleukin-1β, serum and glucocorticoid-inducible protein kinase-1, and nuclear factor kappa B were also upregulated in the contralateral kidneys of UUO rats compared to Sham kidneys, and these effects were reduced by MR blocker EPL.. Our data suggest that the activation of MR is involved in NLRP3/caspase-1 pathway-induced cell pyroptosis in the contralateral kidney of UUO model.

Topics: Animals; Caspase 1; Eplerenone; Kidney; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Ureteral Obstruction

The unilateral ureteral obstruction (UUO) model not only induces renal interstitial fibrosis in the obstructed kidney but also induces injury in the contralateral kidney. We hypothesized that activation of the mineralocorticoid receptor (MR) may induce fibrosis in the early stage of UUO.. Thirty male Sprague-Dawley rats weighting 200 ± 10 g were used in this study and randomly divided into 3 groups: a UUO group, a UUO and eplerenone group, and a sham group. The contralateral kidney and plasma were harvested for further study 10 days after surgery.. The level of plasma aldosterone (869.95 ± 55.851 pg/mL) was significantly higher in the UUO group than that in the sham group (478.581 ± 36.186 pg/mL vs. UUO, p < 0.05). The infiltrated inflammatory cells (F4/80) and deposited collagens were increased significantly in the contralateral kidneys in the UUO group compared to those in the sham group, which were decreased by eplerenone. However, proliferating cell nuclear antigen was increased 2.47 times in the UUO group compared to the sham group in the contralateral kidney (p < 0.01), and those changes are attenuated by eplerenone. The expression of SGK-1 protein and mRNA was upregulated in the contralateral kidney in the UUO group, which is suppressed by eplerenone treatment. NF-κB pathway effecters were also changed markedly in the contralateral kidney in the UUO group and partly reversed by eplerenone.. Aldosterone induces inflammatory cell proliferation via the MR/SGK-1 and NF-κB pathways and eventually leads to fibrosis in the contralateral kidney.

Topics: Actins; Aldosterone; Animals; Cell Proliferation; Collagen; Eplerenone; Fibrosis; Immediate-Early Proteins; Kidney; Male; MAP Kinase Signaling System; Mineralocorticoid Receptor Antagonists; Proliferating Cell Nuclear Antigen; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Spironolactone; Tumor Necrosis Factor-alpha; Up-Regulation; Ureteral Obstruction