Eplerenone Prevents Cardiac Fibrosis by Inhibiting Angiogenesis in Unilateral Urinary Obstruction Rats

Abstract

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 (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 (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 endothelialmesenchymal 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.

Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4

“…2 D and E). These results correlate with previous reports of fibrosis development in the hearts of UUO animals that have been associated with early activation of the Transforming Growth Factor beta (TGF-β)/Smad signaling pathway [ 12 , 16 ].

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Phosphorylation of CaMK and CREB-Mediated Cardiac Aldosterone Synthesis Induced by Arginine Vasopressin in Rats with Myocardial Infarction

“…In addition, aldosterone may enhance collagen I synthesis after activating the MR-dependent pathway in VSMCs, which was able to be blocked by spironolactone [ 22 ]. Furthermore, it was suggested that cardiac fibrosis might be associated with angiogenesis [ 23 ]. Eplerenone, an MR antagonist, was able to attenuate cardiac fibrosis by inhibiting angiogenesis, indicating that aldosterone may be involved in angiogenesis.…”

Unraveling Chronic Cardiovascular and Kidney Disorder through the Butterfly Effect

“…The effectiveness of GLP1 agonists in managing metabolic control and thereby improving cardiorenal pathologies is also notable [ 70 , 84 , 85 , 173 , 174 , 175 , 176 ], particularly as insulin resistance and metabolic disturbances are key in the fibrogenesis pathways that drive cardiorenal syndrome progression. Finerenone and other mineralocorticoid antagonists, beneficial in reducing post-myocardial infarction fibrosis and slowing chronic kidney disease progression, are also promising [ 81 , 82 , 83 , 177 , 178 , 179 ]. Their precise roles in cardiorenal protection are yet to be fully determined.…”