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Role of endoplasmic reticulum stress in renal damage after myocardial infarction
Beatriz Delgado-Valero1, Lucía de la Fuente-Chávez1, Ana Romero-Miranda1
1Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid-Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
Abstract:
Myocardial infarction (MI) is associated with renal alterations resulting in poor outcomes in patients with MI. Renal fibrosis is a potent predictor of progression in patients and is often accompanied by inflammation and oxidative stress; however, the mechanisms involved in these alterations are not well established. Endoplasmic reticulum (ER) plays a central role in protein processing and folding. An accumulation of unfolded proteins leads to ER dysfunction, termed ER stress. Since the kidney is the organ with highest protein synthesis fractional rate, we herein investigated the effects of MI on ER stress at renal level, as well as the possible role of ER stress on renal alterations after MI. Patients and MI male Wistar rats showed an increase in the kidney injury marker neutrophil gelatinase-associated lipocalin (NGAL) at circulating level or renal level respectively. Four weeks post-MI rats presented renal fibrosis, oxidative stress and inflammation accompanied by ER stress activation characterized by enhanced immunoglobin binding protein (BiP), protein disulfide-isomerase A6 (PDIA6) and activating transcription factor 6-alpha (ATF6α) protein levels. In renal fibroblasts, palmitic acid (PA; 50-200 µM) and angiotensin II (Ang II; 10-8 to 10-6M) promoted extracellular matrix, superoxide anion production and inflammatory markers up-regulation. The presence of the ER stress inhibitor, 4-phenylbutyric acid (4-PBA; 4 µM), was able to prevent all of these modifications in renal cells. Therefore, the data show that ER stress mediates the deleterious effects of PA and Ang II in renal cells and support the potential role of ER stress on renal alterations associated with MI.
Insights
Myocardial infarction (MI) triggers kidney damage and fibrosis through endoplasmic reticulum (ER) stress. Inhibiting ER stress protected renal cells from damage, suggesting a therapeutic target for kidney complications post-MI.
Area of Science:
- Nephrology
- Cardiology
- Cellular Biology
Background:
- Myocardial infarction (MI) is linked to kidney alterations, impacting patient outcomes.
- Renal fibrosis, inflammation, and oxidative stress are key features of kidney damage post-MI, but underlying mechanisms remain unclear.
- Endoplasmic reticulum (ER) stress, a cellular response to unfolded proteins, is implicated in various pathologies.
Purpose of the Study:
- To investigate the impact of MI on renal ER stress.
- To explore the role of ER stress in mediating renal alterations following MI.
- To examine the effects of specific cellular stressors on renal cells and the potential of ER stress inhibition.
Main Methods:
- Assessed kidney injury marker NGAL in patients and rats post-MI.
- Analyzed renal fibrosis, oxidative stress, inflammation, and ER stress markers (BiP, PDIA6, ATF6α) in rats 4 weeks post-MI.
- Utilized in vitro models with renal fibroblasts exposed to palmitic acid (PA) and angiotensin II (Ang II).
- Investigated the effects of the ER stress inhibitor 4-phenylbutyric acid (4-PBA).
Main Results:
- Increased NGAL levels were observed in patients and rats post-MI.
- MI-induced renal fibrosis, oxidative stress, and inflammation were associated with ER stress activation.
- PA and Ang II induced extracellular matrix, superoxide anion, and inflammatory marker upregulation in renal cells.
- 4-PBA treatment prevented these deleterious effects in renal cells.
Conclusions:
- ER stress plays a mediating role in the detrimental effects of PA and Ang II on renal cells.
- ER stress activation is a significant factor in renal alterations associated with myocardial infarction.
- Targeting ER stress presents a potential therapeutic strategy for kidney complications following MI.
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