Cardiac Inflammation after Ischemia-Reperfusion of the Kidney: Role of the Sympathetic Nervous System and the Renin-Angiotensin System

Sun

et al. 2021

Front. Cell Dev. Biol.

Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3.

Section: Discussionmentioning

confidence: 99%

Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway

Sun

et al. 2021

Front. Cell Dev. Biol.

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 90%

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

Estrela

Wasinski

Gregnani

et al. 2020

Front. Mol. Biosci.

Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity. Enalapril is an angiotensin I-converting enzyme inhibitor used for the treatment of hypertension, mainly through the reduction of angiotensin II formation, but also through the increase of kinins half-life. Kinin B1 receptor is associated with inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of kinin B1 and B2 receptors can attenuate cisplatin nephrotoxicity. In this study, we tested enalapril treatment as a tool to prevent cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups: control group; cisplatin (20 mg/kg i.p) group; and enalapril (1.5 mg;kg i.p) + cisplatin group. The animals were treated with a single dose of cisplatin and euthanized after 96 h. Enalapril was able to attenuate cisplatin-induced increase in creatinine and urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory cytokines in circulation and kidney. The upregulation of B1 receptor was blocked in enalapril + cisplatin group. Carboxypeptidase M expression, which generates B1 receptor agonists, is blunted by cisplatin + enalapril treatment. The activity of aminopeptidase P, a secondary key enzyme able to degrade kinins, is restored by enalapril treatment. These findings were confirmed in mouse renal epithelial tubular cells, in which enalaprilat (5 µM) was capable of decreasing tubular injury and inflammatory markers. We treated mouse renal epithelial tubular cells with cisplatin (100 µM), cisplatin+enalaprilat and cisplatin+enalaprilat+apstatin (10 µM). The results showed that cisplatin alone decreases cell viability, cisplatin plus enalaprilat is able to Estrela et al. ACE-Inhibitor Attenuates Cisplatin Nephrotoxicity restore cell viability, and cisplatin plus enalaprilat and apstatin decreases cell viability. In the present study, we demonstrated that enalapril prevents cisplatin nephrotoxicity mainly by preventing the upregulation of B1 receptor and carboxypeptidase M and the increased concentrations of kinin peptides through aminopeptidase activity restoration.

“…It is well known that not all cytokines are involved at all stages of inflammation, but some of them do mediate both acute and chronic responses. This is the case of TNF-α, IL-1 (α and β) and IL-6 [ 229 ], which are some of the most studied ones and have been suggested to have an important role in inflammatory modulation during CRS due to its extremely potent proinflammatory effects [ 94 , 230 , 231 , 232 ].…”

Section: Mechanisms Involved In Fibrosis Progressionmentioning

confidence: 99%

Fibrosis, the Bad Actor in Cardiorenal Syndromes: Mechanisms Involved

Delgado-Valero

Cachofeiro

Martínez‐Martínez

2021

Cells

Cardiorenal syndrome is a term that defines the complex bidirectional nature of the interaction between cardiac and renal disease. It is well established that patients with kidney disease have higher incidence of cardiovascular comorbidities and that renal dysfunction is a significant threat to the prognosis of patients with cardiac disease. Fibrosis is a common characteristic of organ injury progression that has been proposed not only as a marker but also as an important driver of the pathophysiology of cardiorenal syndromes. Due to the relevance of fibrosis, its study might give insight into the mechanisms and targets that could potentially be modulated to prevent fibrosis development. The aim of this review was to summarize some of the pathophysiological pathways involved in the fibrotic damage seen in cardiorenal syndromes, such as inflammation, oxidative stress and endoplasmic reticulum stress, which are known to be triggers and mediators of fibrosis.