Melatonin fine-tunes intracellular calcium signals and eliminates myocardial damage through the IP3R/MCU pathways in cardiorenal syndrome type 3

Background: Renal ischemia/reperfusion induces a systemic inflammatory response that is directly related to the development of cardiac hypertrophy due to cardiorenal syndrome type 3. Classic inflammatory pathways have been extensively investigated in cardiovascular diseases, including the participation of inflammasome in caspase-1-dependent IL-1β cleavage. Objective: In this study, we aimed to understand how lack of caspase-1 would impact the hypertrophic and apoptotic response in the heart after renal ischemia/reperfusion. Methods: Wildtype and caspase-1 knockout animals were submitted to a renal ischemia/reperfusion protocol. Briefly, left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 15 days. Gene expression was analysed by Real-Time PCR. Caspase activity was also evaluated. Results: Lack of caspase-1 led to a more pronounced cardiac hypertrophy in mice subjected to renal ischemia-reperfusion. Such hypertrophic process was accompanied by increased activity of caspase3/7 and 9, indicating apoptosis initiation in an IL-1β- independent manner. Conclusion: Our data corroborate important findings on the role of caspase-1 in the development of cardiac hypertrophy and remodeling.

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BI-1 ameliorates myocardial injury by activating the mitochondrial unfolded protein response and FUNDC1-related mitophagy in cardiorenal syndrome type 3

Cellular Signalling ◽

10.1016/j.cellsig.2021.110218 ◽

2021 ◽

pp. 110218

Author(s):

Jin Wang ◽

Xiaohua Wang ◽

Wenjuan Du ◽

Zhe Xue ◽

Wei Huang ◽

...

Keyword(s):

Unfolded Protein Response ◽

Myocardial Injury ◽

Cardiorenal Syndrome ◽

Syndrome Type ◽

Unfolded Protein ◽

Protein Response ◽

Type 3 ◽

Mitochondrial Unfolded Protein Response

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Cardiorenal Syndrome Type 3

Critical Care Nephrology ◽

10.1016/b978-0-323-44942-7.00113-8 ◽

2019 ◽

pp. 695-701.e2

Author(s):

Teena P. Zachariah ◽

Vasanthi Balaraman ◽

R. John Crew

Keyword(s):

Cardiorenal Syndrome ◽

Syndrome Type ◽

Type 3

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.630412 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jin Wang ◽

Xuefeng Sun ◽

Xu Wang ◽

Shaoyuan Cui ◽

Ran Liu ◽

...

Keyword(s):

Signaling Pathway ◽

Cardiac Dysfunction ◽

Specific Inhibitor ◽

Cardiorenal Syndrome ◽

Mtor Signaling ◽

Mitochondrial Bioenergetics ◽

Syndrome Type ◽

Mtor Signaling Pathway ◽

Bias Analysis ◽

Type 3

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.

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