Pathological cardiac remodeling occurs early in CKD mice from unilateral urinary obstruction, and is attenuated by Enalapril

Abstract

Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.

Cardiac Remodeling in Chronic Kidney Disease

“…In addition, unilateral ureteral obstruction (UUO) can induce some cardiac hypertrophy and fibrosis [79,92]. However, since UUO does not cause renal failure in the presence of a non-injured contralateral kidney, the model is probably not suitable to induce a severe cardiac phenotype.…”

Angiotensin-Converting Enzyme Inhibitor Protects Against Cisplatin Nephrotoxicity by Modulating Kinin B1 Receptor Expression and Aminopeptidase P Activity in Mice

“…In the present study, while no strong changes in renal AT1R expression were observed in enalapril-treated mice, part of the reduction in renal inflammation and damage can also be due to the expected reduction of AngII peptide, since enalapril is a strong ACE inhibitor. AngII has been associated to kidney inflammation in several models (Theuer et al, 2002;Altunoluk et al, 2006;Benigni et al, 2011;Nagasawa et al, 2012;Kanda et al, 2016;Ham et al, 2018;Panico et al, 2019), and the FIGURE 7 | Carboxypeptidase M mRNA expression in renal tissue and mouse epithelial tubular cells. The panels show CPM mRNA expression (A) in mice 24 h after treatment with cisplatin or cisplatin plus enalapril and CPM mRNA expression (B) in mouse tubular cells after treatment with cisplatin or enalaprilat plus cisplatin.…”

“…Studies have revealed that ACE influences the regulation of both kinin receptors in vascular smooth muscle cells (Ignjacev-Lazich et al, 2005). Moreover, it has already been shown that ACE inhibition protects against some types of renal disease (Ghosh et al, 2009(Ghosh et al, , 2012Vejakama et al, 2012;Ding et al, 2014;Ham et al, 2018;Panico et al, 2019), including cisplatin-induced kidney disfunction (El-Sayed el et al, 2008), but only renal function and reactive oxygen species were assessed in this work. Given that (a) inflammation has an important role in cisplatin nephrotoxicity; (b) AngII influences the regulation of inflammation-related genes; and (c) ACE inhibition reduces kinin degradation, we decided to verify whether the protective effect of ACE inhibition on the attenuation of cisplatin nephrotoxicity is related to KKS regulation.…”

Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets

“…Prolyl hydroxylase (PHD) inhibitors, stabilizers of hypoxia-inducible factors (HIFs), have been used to treat acute organ injuries such as renal ischemia-reperfusion, myocardial infarction, and, in some contexts, chronic kidney disease [ 93 ]. Enarodustat (PHD inhibitor) proved to reduce cardiac hypertrophy and fibrosis in a unilateral urinary obstruction (UUO) model in mice [ 94 ]. Moreover, enarodustat counteracted kidney fibrosis reducing pro-inflammatory cytokine expression, apoptosis, and improving capillary density in a nephrectomy model [ 93 ].…”