The CaMKII inhibitory peptide AIP alleviates renal fibrosis through the TGF-β/Smad and RAF/ERK pathways.

Abstract

Renal fibrosis is characterized by the excessive deposition of extracellular matrix that destroys and replaces the functional renal parenchyma, ultimately leading to organ failure. It is a common pathway by which chronic kidney disease (CKD) can develop into end-stage renal disease (ESRD), which has high global morbidity and mortality, and there are currently no good therapeutic agents available. CaMKII has been indicated to be closely related to the occurrence of renal fibrosis, and its specific inhibitory peptide AIP, was shown to directly bind the active site of CaMKII. In this study, we examined the effect of AIP on the progression of renal fibrosis and its possible mechanism. The results showed that AIP could inhibit the expression of the fibrosis markers Fibronectin, Collagen I, MMP2 and α-SMA in vivo and in vitro. Further analysis revealed that AIP could inhibit the expression of various epithelial-to-mesenchymal transformation (EMT)-related markers, such as Vimentin and Snail 1, in vivo and in vitro. Mechanistically, AIP could significantly inhibit the activation of CaMKII, Smad 2, Raf and ERK in vitro and in vivo and reduce the expression of TGF-β in vivo. These results suggested that AIP could alleviate renal fibrosis by inhibiting CaMKII and blocking activation of the TGF-β/Smad2 and RAF/ERK pathways. Our study provides a possible drug candidate and demonstrates that CaMKII is a potential pharmacological target for the treatment of renal fibrosis. Significance Statement We have demonstrated that AIP significantly attenuated TGF-β1-induced fibrogenesis and ameliorated UUO-induced renal fibrosis through the CaMKII/TGF-β/Smad and CaMKII/RAF/ERK signaling pathways in vitro and in vivo. Our study provides a possible drug candidate and demonstrates that CaMKII can be a potential pharmacological target for the treatment of renal fibrosis.