CaMKII -Calcium (Ca2+)/calmodulin (CaM)-dependent protein kinase II CKD -chronic kidney disease Col I -Collagen I ECM -extracellular matrix EMT -epithelial-to-mesenchymal transformation ERK -extracellular regulated protein kinases ESRD -end-stage renal disease FBS -fetal bovine serum FMT -fibroblast-to-myofibroblast transformation FN -Fibronectin GAPDH -glyceraldehyde-3-phosphate dehydrogenase MAPK -mitogen-activated protein kinase MMP2 -matrix metalloproteinase 2 PKD -polycystic kidney disease ROS -Reactive oxygen species Scr -serum creatinine TGF-β1 -transforming growth factor-β1 UUO -unilateral ureteral obstruction Vim -Vimentin α-SMA -α-smooth muscle actin e) Recommended section: 1) Cellular and Molecular This article has not been copyedited and formatted. The final version may differ from this version.
Pulmonary fibrosis (PF), which is characterized by enhanced extracellular matrix (ECM) deposition, is an interstitial lung disease that lacks an ideal clinical treatment strategy. It has an extremely poor prognosis, with an average survival of 3-5 years after diagnosis. Our previous studies have shown that the antioxidant peptide DR8 (DHNNPQIR-NH 2 ), which is extracted and purified from rapeseed, can alleviate PF and renal fibrosis. However, natural peptides are easily degraded by proteases in vivo, which limits their potency. We have since synthesized a series of DR8 analogs based on amino acid scanning substitution. DR7dA (DHNNPQ (D-alanine) R-NH 2 ) is an analog of DR8 in which L-isoleucine (L-Ile) is replaced with D-alanine (D-Ala), and its half-life is better than that of DR8. In the current study, we verified that DR7dA ameliorated TGF-β1-induced fibrogenesis and bleomycin-induced PF. The results indicated that DR7dA reduced the protein and mRNA levels of TGF-β1-target genes in TGF-β1-induced models. Surprisingly, DR7dA blocked fibrosis in a lower concentration range than DR8 in cells. In addition, DR7dA ameliorated tissue pathological changes and ECM accumulation in mice. BLM caused severe oxidative damage, but administration of DR7dA reduced oxidative stress and restored antioxidant defense. Mechanistic studies suggested that DR7dA inhibits ERK, P38 and JNK phosphorylation in vivo and in vitro. All results indicated that DR7dA attenuated PF by inhibiting ECM deposition and oxidative stress via blockade of the MAPK pathway. Hence, compared with its parent peptide, DR7dA has higher druggability and could be a candidate compound for PF treatment in the future.
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