Exosomal circ_DLGAP4 promotes diabetic kidney disease progression by sponging miR-143 and targeting ERBB3/NF-κB/MMP-2...

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Diabetic kidney disease (DKD) is a major complication of diabetes, increasing cardiovascular risk and mortality.
• Exosomal circular RNAs (circRNAs) are implicated in disease pathology, but their role in DKD remains unclear.
• Circular RNA DLGAP4 (circ_DLGAP4) has been linked to ischemic stroke, suggesting potential roles in other conditions.

Purpose of the Study:

• To investigate the role and mechanism of exosomal circ_DLGAP4 in the progression of diabetic kidney disease (DKD).
• To explore the regulatory pathway involving circ_DLGAP4, miR-143, and ERBB3 in mesangial cells (MCs) and DKD models.

Main Methods:

• Quantification of exosomal circ_DLGAP4 in high glucose-treated MCs, DKD patients, and DKD rat models.
• In vitro assays to assess the effects of circ_DLGAP4 on MC proliferation and fibrosis.
• Bioinformatic analysis to predict circ_DLGAP4 targets, followed by validation of circ_DLGAP4/miR-143 and miR-143/ERBB3 interactions.
• In vivo studies in DKD rat models to confirm the role of circ_DLGAP4 in disease progression.

Main Results:

• Exosomal circ_DLGAP4 levels were significantly elevated in DKD conditions.
• Overexpression of circ_DLGAP4 promoted MC proliferation and fibrosis, while its inhibition reversed these effects.
• Circ_DLGAP4 acted as a molecular sponge for miR-143, leading to increased ERBB3 expression and activation of the ERBB3/NF-κB/MMP-2 axis.
• In vivo, circ_DLGAP4 overexpression exacerbated DKD progression by modulating the miR-143/ERBB3/NF-κB/MMP-2 pathway.

Conclusions:

• Exosomal circ_DLGAP4 plays a critical role in promoting DKD progression.
• The circ_DLGAP4/miR-143/ERBB3/NF-κB/MMP-2 axis represents a novel mechanism in DKD pathogenesis.
• Exosomal circ_DLGAP4 may serve as a potential diagnostic biomarker and therapeutic target for DKD.