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1.
Cells ; 13(6)2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38534333

RESUMEN

The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-ß-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.


Asunto(s)
Quistes , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Humanos , Factor de Necrosis Tumoral alfa , Fibrosis
2.
Int J Mol Sci ; 24(9)2023 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-37175958

RESUMEN

Contrast-induced acute kidney injury (CI-AKI) is manifested by an abrupt decline in kidney function as a consequence of intravascular exposure to contrast media. With the increased applicability of medical imaging and interventional procedures that utilize contrast media for clinical diagnosis, CI-AKI is becoming the leading cause of renal dysfunction. The pathophysiological mechanism associated with CI-AKI involves renal medullary hypoxia, the direct toxicity of contrast agents, oxidative stress, apoptosis, inflammation, and epigenetic regulation. To date, there is no effective therapy for CI-AKI, except for the development of strategies that could reduce the toxicity profiles of contrast media. While most of these strategies have failed, evidence has shown that the proper use of personalized hydration, contrast medium, and high-dose statins may reduce the occurrence of CI-AKI. However, adequate risk predication and attempts to develop preventive strategies can be considered as the key determinants that can help eliminate CI-AKI. Additionally, a deeper understanding of the pathophysiological mechanism of CI-AKI is crucial to uncover molecular targets for the prevention of CI-AKI. This review has taken a step further to solidify the current known molecular mechanisms of CI-AKI and elaborate the biomarkers that are used to detect early-stage CI-AKI. On this foundation, this review will analyze the molecular targets relating to apoptosis, inflammation, oxidative stress, and epigenetics, and, thus, provide a strong rationale for therapeutic intervention in the prevention of CI-AKI.


Asunto(s)
Lesión Renal Aguda , Medios de Contraste , Humanos , Medios de Contraste/uso terapéutico , Epigénesis Genética , Lesión Renal Aguda/terapia , Estrés Oxidativo , Inflamación , Factores de Riesgo
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