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

Abstract

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.

Experimental Cardiorenal Syndrome Type 3: What Is Known so Far?

“…A recent study by Wang and colleagues [ 18 ] aimed to identify the primary stimulus of myocardial damage in CRS type 3. It was emphasized that inflammation and oxidative stress indeed induce cardiac dysfunction.…”

Mitochondrial Bioenergetic and Proteomic Phenotyping Reveals Organ-Specific Consequences of Chronic Kidney Disease in Mice

“…Nonetheless, there are several studies that have reported observations related to the current work. For example, isolated cardiac myocytes from C57BL6J mice following acute kidney injury (AKI) demonstrated an increase in ROS production utilizing a ROS-based fluorescent probe (DCFHA-DA) [ 48 ]; and in another study in rats with nephrectomies, cardiomyocytes displayed increased vulnerability to oxidant-induced death [ 22 ]. It is believed that increased ROS production within the mitochondria can cause oxidative post-translational modifications to respiratory proteins and mtDNA that cumulatively impair the organelle’s function.…”

Mitochondrial Dysfunction: An Emerging Link in the Pathophysiology of Cardiorenal Syndrome

“…CRS3 refers to a CRS subtype in which the onset of AKI leads to the progression of acute cardiac injury or dysfunction (9). Proteomic analysis of CRS3 rats showed alterations in myocardial pyruvate metabolism, glyoxylate and dicarboxylic acid metabolism, starch and sucrose metabolism, and amino acid biosynthesis, with 23 proteins enriched in signaling pathways related to mitochondrial function, suggesting that AKI may affect cardiomyocyte metabolism or mitochondrial bioenergy (23). Growth factor receptor-binding protein 2 (Grb2) is a regulator of AKI-related myocardial injury, and Grb2 activation promotes mitochondrial metabolic disorders in cardiomyocytes by inhibiting the Akt/mTOR signaling pathway.…”

“…Growth factor receptor-binding protein 2 (Grb2) is a regulator of AKI-related myocardial injury, and Grb2 activation promotes mitochondrial metabolic disorders in cardiomyocytes by inhibiting the Akt/mTOR signaling pathway. Additionally, the administration of Grb2-specific inhibitors reverses myocardial pathological changes in the context of AKI (23). Furthermore, the dysregulation of mitochondrial dynamics caused by increased Drp1 expression and cardiac apoptosis plays an important role in AKI-induced myocardial injury (147,148).…”

“…Furthermore, all the above-mentioned pathological factors in CRS damage the mitochondria in distal organs through circulatory effects (21)(22)(23), suggesting that mitochondria play a connecting role in cardiorenal interaction, and may be a core link in CRS progression (Figure 2). However, the specific mechanism and evidence have not been well summarized.…”