No abstract

Background/Aims: Adipose-derived stem cells (ASCs) belong to mesenchymal stem cells and may play a potential role as seeding cells in stem cell transplantation. To be able to exploit stem cells as therapeutic tool, their defects in some important cellular functions, such as low survival rate and cellular activity, should be considered. This is especially the case for stem cells that are intended for transplantation. Of note, stem cell responses to hormones should be considered since estrogen is known to play a critical role in stem cell behavior. However, different impacts of the estrogen receptor (ER) types α and β have not been fully determined in ASC function. In this study, we investigated effects of ERα and ERβ on ASC proliferation, migration, as well as in adipogenesis. Methods: ASCs obtained from mice were cultured with 100nM ERα or ERβ agonist PPT and DPN, respectively. The ERα and ERβ antagonist ICI 182,780 (100nM) was used as control. Results: Compared to ERβ, ERα appears more potent in improving ASC proliferation and migration. Investigation of adipogenesis revealed that ERβ played a significant role in suppressing ASC-mediated brown tissue adipogenesis which is in contrast to ERα. These results correlated with reduced mRNA expression of UCP-1, PGC-1α and PPAR-γ. Conclusions: ERα plays a more critical role in promoting ASC proliferation and migration while ERβ is more potent in suppressing ASC brown adipose tissue differentiation mediated by decreased UCP-1, PGC-1α and PPAR-γ expression.

Ischemia reperfusion (IR) can lead to acute kidney injury and can be complicated by acute lung injury, which is one of the leading causes of acute kidney injury-related death. Peptidyl arginine deiminase-4 (PAD4) is a member of the PAD enzyme family and plays a critical role in inflammatory reactions and neutrophil extracellular trap formation in a variety of pathological conditions. It has been reported that PAD4 inhibition can protect certain organs from ischemic injury. In this study, we aimed to understand the mode of action of PAD4 in renal ischemia-reperfusion-mediated acute lung injury. Bilateral renal pedicle occlusion was induced for 30 min followed by reperfusion for 24 h. A specific inhibitor of PAD4, GSK484, was delivered via intraperitoneal injection to alter the PAD4 activity. The pulmonary PAD4 expression, pulmonary impairment, neutrophil infiltration, Cit-H3 expression, neutrophil extracellular trap formation, inflammatory cytokine secretion, and pulmonary apoptosis were analyzed. We found that renal ischemia reperfusion was associated with pulmonary pathological changes and increases in neutrophil infiltration, neutrophil extracellular trap formation, and inflammatory cytokine secretion in the lungs of the recipient animals. Suppression of PAD4 by GSK484 reduced remote lung injury by mitigating neutrophil infiltration, neutrophil extracellular trap formation, apoptosis, and inflammatory factor secretion. Our findings demonstrate that specific PAD4 inhibition by GSK484 may be an effective strategy to attenuate distant lung injury complicating renal ischemia-reperfusion injury.