Calcium Ion Attenuates Transforming Growth Factor β1-Induced Extracellular Matrix Accumulation by Inducing Smad2 Degradation through the Proteasome Pathway

Extracellular Ca²⁺ is the first ligand that has been confirmed to function by activating the calcium-sensing receptor (CaSR), a member of G-protein coupled receptors. CaSR controls not only calcium homeostasis, but also plays a pivotal role in many cellular processes such as cell proliferation and apoptosis; moreover, it is implicated in the development of cardiovascular diseases. TGF-β/Smads signaling pathway is a classical pathway of renal fibrosis. Here we used a culture of mesangial cells to evaluate the mechanisms of the renoprotective effects of Ca²⁺. We found that Ca²⁺ inhibits TGF-β-induced phosphorylation of Smad2 and deposition of fibronectin (FN), in turn, down-regulation of FN and phosphorylation of Smad2 was closely related to the degradation of Smad2 through the proteasomal pathway. We found that Ca²⁺ only downregulates the expression of Smad2 at the protein level, but has no effect on its gene expression. However, Ca²⁺ could downregulate TGF-β-induced expression of FN both at the protein and gene level. Hence, Smad2 acts as a transcription factor of FN, and its degradation definitely inhibits the expression of its target gene FN.