Myocardial
fibrosis is a major complication of
diabetic cardiomyopathy (DCM) that is primarily caused by cardiac fibroblasts that are highly activated by persistent hyperglycemic stimulation, resulting in excessive
collagen deposition.
Calcium sensing receptor (CaSR) is a member of the G protein‑coupled receptor superfamily and regulates intracellular
calcium concentrations, which are associated with numerous diseases, including
myocardial infarction,
tumors and
pulmonary hypertension. However, whether CaSR participates in the pathological process of myocardial
fibrosis in DCM remains unknown. The present study aimed to investigate the mechanism via which CaSR regulates high
glucose (HG)‑induced cardiac
fibrosis in vitro. HG treated‑cardiac fibroblast (CFs) were used and western blotting, immunoprecipitation, Cell Counting Kit‑8 assay, ELISA and transfection technology were performed to examine the role of CaSR. In the HG group, treatment with HG increased CaSR, α‑smooth muscle actin, collagen I/III and matrix metalloproteinase 2/9 expression and enhanced autophagosome generation and CF proliferation. Furthermore, CaSR activation upregulated the expression of Smad
ubiquitin regulatory factor 2 (Smurf2), which led to increased intracellular Ca2+ concentrations, increased ubiquitination levels of SKI like proto‑oncogene and Smad7 and autophagy activation. Furthermore, the CaSR agonist (R568) or the CaSR inhibitor (
Calhex231) and Smurf2‑small interfering
RNA promoted or inhibited HG‑induced alterations, including the enhanced and weakened effects, respectively. Taken together, the results from the present study suggested that increased CaSR expression in CFs activated the Smurf2‑ubiquitin
proteasome and autophagy, causing excessive CF proliferation and extensive
collagen deposition, which resulted in HG‑induced myocardial
fibrosis. These findings indicated a novel pathogenesis of DCM and may provide a novel strategy for the diagnosis and treatment of DCM.