Alamandine via MrgD receptor attenuates pulmonary fibrosis via NOX4 and autophagy pathway

Abstract

Alamandine (ALA) and its receptor MrgD were recently identified as components of the renin-angiotensin system (RAS), which confer protection against cardio-fibrosis and renal-fibrosis. However, the effects of ALA on pulmonary fibrosis are unknown. This study was designed to serve two goals: (1) to evaluate ALA/MrgD axis ability in the prevention of Angiotensin Ⅱ (Ang Ⅱ)-induced pulmonary fibrosis in fibroblasts. (2) to determine the effect of ALA in bleomycin (BLM) treated C57B/6 mice. In vivo experiments revealed that the treatment of C57B/6 mice with ALA prevented BLM-induced fibrosis and these findings were similar to those reported for pirfenidone. The anti-fibrosis actions of ALA were mediated via alleviation of oxidative injury and autophagy induction. In addition, in vitro studies revealed that ALA treatment attenuated Ang Ⅱ-induced α-collagen I, CTGF and α-SMA production in fibroblast which was blocked by D-Pro7-Ang-(1-7), an MrgD antagonist. This led to alleviation of oxidative injury and induction of autophagy similar to that reported for rapamycin. This study demonstrated that ALA via MrgD receptor reduced pulmonary fibrosis through attenuation of oxidative injury and induction of autophagy.

Swertiamarin attenuates paraquat-induced pulmonary epithelial-like cell apoptosis via NOX4-mediated regulation of redox and mitochondrial function

“…The main sources of PQ-induced ROS production are PQ metabolism in microsomal enzyme systems and mitochondria and the activation of NOX4 in inflammatory and lung target cells (Pourgholamhossein et al, 2018). Recently, targeting NOX4 seemed to be a promising strategy to alleviate experimental lung fibrosis (Sato et al, 2016;Du et al, 2021;Liu et al, 2021). Our results indicated that reducing oxidant formation and oxidative stress might be mechanisms by which the antiapoptotic effect of STM is mediated.…”

Alamandine/MrgD axis prevents TGF-β1-mediated fibroblast activation via regulation of aerobic glycolysis and mitophagy

“…Studies have demonstrated that ALA plasmatic concentrations are decreased in IPF patients [24] and that ALA alleviates BLM-induced mice lung fibrosis and angiotensin II (Ang II)-induced fibroblast activation by binding to the MrgD receptor [16,19]. Other studies found that myocardial, vascular, and liver fibrosis could be inhibited by ALA [17,18,25,26].…”

“…Alamandine (ALA), a novel member of the reninangiotensin-aldosterone system (RAAS), exerts antiinflammation and anti-fibrosis effects via the ALA/MrgD axis [16,17]. Our previous studies have demonstrated the anti-fibrosis and autophagy-modulating effects of ALA in the lungs and liver [18,19]. However, further studies are needed to investigate whether ALA protects against LF activation by regulating Parkin/LC3-mediated mitophagy.…”

Hormonal Regulation of Renal Fibrosis

“…Ang 1-7 can then be cleaved to another angiotensin peptide, alamandin. Ang 1-7 and alamandin have their own specific receptors, MAS1 and MrgD, which demonstrate effects similar to those of Ang II through the AT2 receptor—anti-inflammatory, antifibrotic and vasodilating [ 61 , 62 ]. Ang 1-7 suppresses the development of oxidative stress in CKD models by inhibiting Nox4 expression [ 63 ] and increasing catalase activity in the kidneys [ 64 ].…”