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Influence of the interaction between Ac‑SDKP and Ang II on the pathogenesis and development of silicotic fibrosis
Yi Zhang1, Fang Yang2, Yan Liu1
1Basic Medical College, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China.
Abstract:
N‑acetyl‑seryl‑aspartyl‑lysyl‑proline (Ac‑SDKP) is a natural tetrapeptide that is released from thymosin β4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin‑angiotensin system, angiotensin‑converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac‑SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac‑SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac‑SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac‑SDKP decreased. Ac‑SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac‑SDKP treatment had an anti‑fibrotic effect in vivo. Compared with the silicosis group, the expression of α‑smooth muscle actin (α‑SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase‑1 (MMP‑1) expression and the MMP‑1/tissue inhibitor of metalloproteinases‑1 (TIMP‑1) ratio was increased in the Ac‑SDKP treatment group. In vitro, pre‑treatment with Ac‑SDKP or valsartan attenuated the expression of α‑SMA, Col I, Fn and AT1 in Ang II‑induced fibroblasts. In addition, MMP‑1 expression and the MMP‑1/TIMP‑1 ratio were significantly higher in Ac‑SDKP and valsartan pre‑treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac‑SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac‑SDKP protects against silicotic fibrosis by inhibiting Ang II‑induced myofibroblast differentiation and extracellular matrix production.
Insights
N‑acetyl‑seryl‑aspartyl‑lysyl‑proline (Ac‑SDKP) counteracts silicotic fibrosis by inhibiting the angiotensin-converting enzyme (ACE) pathway. Ac-SDKP treatment reduced fibrotic markers and myofibroblast differentiation in both in vivo and in vitro models of silicosis.
Area of Science:
- Pulmonary Medicine
- Fibrosis Research
- Biochemistry
Background:
- Silicotic fibrosis is a progressive lung disease.
- The renin-angiotensin system (RAS), particularly angiotensin II (Ang II), plays a role in fibrosis.
- N‑acetyl‑seryl‑aspartyl‑lysyl‑proline (Ac‑SDKP) is a natural peptide that interacts with the RAS.
Purpose of the Study:
- To investigate the relationship between Ac‑SDKP, the ACE/Ang II/AT1 axis, and silicotic fibrosis.
- To evaluate the therapeutic potential of Ac‑SDKP in silicotic fibrosis.
Main Methods:
- In vivo studies using a rat model of silicosis treated with Ac‑SDKP.
- In vitro studies using Ang II-induced lung fibroblasts pretreated with Ac‑SDKP or valsartan.
- Analysis of key fibrotic markers, including α‑smooth muscle actin (α‑SMA), Collagen I (Col I), Fibronectin (Fn), and AT1 receptor expression.
Main Results:
- Silicosis development was associated with increased ACE/Ang II/AT1 expression and decreased Ac‑SDKP levels.
- Ac‑SDKP treatment demonstrated anti-fibrotic effects in vivo, downregulating α‑SMA, Col I, Fn, and AT1.
- Ac‑SDKP and valsartan inhibited Ang II-induced myofibroblast differentiation and extracellular matrix production in vitro.
- Ac‑SDKP treatment increased MMP-1 expression and the MMP-1/TIMP-1 ratio, indicating matrix remodeling.
Conclusions:
- An imbalance between Ac‑SDKP and the ACE/Ang II/AT1 axis promotes silicotic fibrosis.
- Ac‑SDKP exhibits protective effects against silicotic fibrosis.
- Ac‑SDKP acts by inhibiting Ang II-induced myofibroblast differentiation and extracellular matrix production.
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