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- Title
Mitochondrial Impairment: A Link for Inflammatory Responses Activation in the Cardiorenal Syndrome Type 4.
- Authors
Amador-Martínez, Isabel; Aparicio-Trejo, Omar Emiliano; Bernabe-Yepes, Bismarck; Aranda-Rivera, Ana Karina; Cruz-Gregorio, Alfredo; Sánchez-Lozada, Laura Gabriela; Pedraza-Chaverri, José; Tapia, Edilia
- Abstract
Cardiorenal syndrome type 4 (CRS type 4) occurs when chronic kidney disease (CKD) leads to cardiovascular damage, resulting in high morbidity and mortality rates. Mitochondria, vital organelles responsible for essential cellular functions, can become dysfunctional in CKD. This dysfunction can trigger inflammatory responses in distant organs by releasing Damage-associated molecular patterns (DAMPs). These DAMPs are recognized by immune receptors within cells, including Toll-like receptors (TLR) like TLR2, TLR4, and TLR9, the nucleotide-binding domain, leucine-rich-containing family pyrin domain-containing-3 (NLRP3) inflammasome, and the cyclic guanosine monophosphate (cGMP)–adenosine monophosphate (AMP) synthase (cGAS)–stimulator of interferon genes (cGAS-STING) pathway. Activation of these immune receptors leads to the increased expression of cytokines and chemokines. Excessive chemokine stimulation results in the recruitment of inflammatory cells into tissues, causing chronic damage. Experimental studies have demonstrated that chemokines are upregulated in the heart during CKD, contributing to CRS type 4. Conversely, chemokine inhibitors have been shown to reduce chronic inflammation and prevent cardiorenal impairment. However, the molecular connection between mitochondrial DAMPs and inflammatory pathways responsible for chemokine overactivation in CRS type 4 has not been explored. In this review, we delve into mechanistic insights and discuss how various mitochondrial DAMPs released by the kidney during CKD can activate TLRs, NLRP3, and cGAS-STING immune pathways in the heart. This activation leads to the upregulation of chemokines, ultimately culminating in the establishment of CRS type 4. Furthermore, we propose using chemokine inhibitors as potential strategies for preventing CRS type 4.
- Subjects
CARDIO-renal syndrome; CYCLIC guanylic acid; CHRONIC kidney failure; CELL receptors; INFLAMMATION; CHEMOKINE receptors; KOUNIS syndrome
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 21, p15875
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms242115875