Reduced expression of PDZK1 mediates fibroblast activation and cardiac fibrosis via EGFR phosphorylation in diabetic cardiomyopathy.

AIMS: To clarify the molecular mechanisms underlying PDZK1-mediated regulation of cardiac fibroblast (CF) activation and cardiac fibrosis in diabetic cardiomyopathy (DCM).

MATERIALS AND

METHODS

DCM models were constructed using db/db mice fed a high-fat diet (HFD) and C57BL/6 mice induced by multiple low-dose streptozotocin (STZ) combined with HFD. PDZK1 expression in myocardial tissues was detected via molecular assays; cardiac function was evaluated using echocardiography, and cardiac fibrosis was assessed by histopathological staining. The effects of PDZK1 knockout and overexpression on cardiac dysfunction and fibrosis were systematically evaluated, and the molecular interaction between PDZK1 and epidermal growth factor receptor (EGFR) was explored through co-immunoprecipitation and phosphorylation analysis.

KEY FINDINGS: PDZK1 expression was significantly downregulated in myocardial tissues of DCM mice compared with controls. PDZK1 knockout further aggravated STZ/HFD-induced cardiac dysfunction and excessive cardiac fibrosis, whereas PDZK1 overexpression markedly ameliorated these pathological changes in diabetic mice. Mechanistically, PDZK1 specifically interacted with the carboxyl terminus of EGFR via its PDZ1 and PDZ3 domains, thereby inhibiting EGFR phosphorylation at critical tyrosine residues and subsequent activation of downstream Akt signaling, which in turn suppressed CF activation and extracellular matrix deposition. This novel PDZK1-EGFR interaction in the context of DCM is reported for the first time.

SIGNIFICANCE: These findings identify PDZK1 as a key regulator of cardiac fibrosis in DCM through modulation of the PDZK1-EGFR-Akt pathway, highlighting its potential as a promising anti-fibrotic therapeutic target for DCM treatment.