ENaCs as Both Effectors and Regulators of MiRNAs in Lung Epithelial Development and Regeneration

Abstract

Epithelial sodium channels (ENaC) play an important role in re-absorbing excessive luminal fluid by building up an osmotic Na⁺ gradient across the tight epithelium in the airway, the lung, the kidney, and the colon. The ENaC is a major pathway for retention of salt in kidney too. MicroRNAs (miRs), a group of non-coding RNAs that regulate gene expression at the post-transcriptional level, have emerged as a novel class of regulators for ENaC. Given the ENaC pathway is crucial for maintaining fluid homeostasis in the lung and the kidney and other cavities, we summarized the cross-talk between ENaC and miRs and recapitulated the underlying regulatory factors, including aldosterone, transforming growth factor-β1, and vascular endothelial growth factor-A in the lung and other epithelial tissues/organs. We have compared the profiling of miRs between normal and injured mice and human lungs, which showed a significant alteration in numerous miRs in mouse models of LPS and ventilator induced ARDS. In addition, we reiterated the potential regulation of the ENaC by miRs in stem/ progenitor cell-based re-epithelialization, and identified a promising pharmaceutic target of ENaC for removing edema fluid in ARDS by mesenchymal stem cells-released paracrine. In conclusion, it seems that the interactions between miRs and scnn1s/ENaCs are critical for lung development, epithelial cell turnover in adult lungs, and re-epithelialization for repair.

Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility

“…ENaC proteins are located in the apical membranes of tight epithelia, and they are the major pathways for the entry of Na ϩ . As such, they play an important role in maintaining the proper depth of airway and alveolar lining fluids, the reabsorption of edema fluid in injured lungs, and the regulation of salt retention in the collecting tubules (6,14,18,28,38,39,50,64). Proteolysis is an important regulatory mechanism of ENaC function (36,63,65,67,70,99).…”

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

“…However, the underlying mechanism by which BMMSCs attenuate ALI have not yet been fully clarified. This attenuation might be associated with paracrine functions of BM-MSCs, with moderation of the inflammatory reaction that accompanies ALI, with variable anti-bacterial effects, or by adoption of the phenotype of lung cells [20][21][22][23]. In addition, BM-MSCs can serve as cellular vehicles for gene delivery and can target protective genes to injured lung tissues, which enhances their therapeutic effects [20,22].…”

Bone marrow mesenchymal stem cell‐conditioned medium facilitates fluid resolution via miR‐214‐activating epithelial sodium channels

“…47 Among the three main subunits, α-ENaC is critical for channel functionality and the mice knocked out α-ENaC gene died for the insufficient AFC during the perinatal period, while β and γ ENaC are regulatory subunits and can maximize the channel function. 48,49 Many studies reported the therapeutic effects of MSCs on ALI through cytokines; however, information on the exact roles of MSC-CM-derived miRNAs in lung edema during ALI and the relative mechanisms of altered ion transport are still scarce. [50][51][52][53] In our study, we explored a cell-free therapy method and investigated the impacts of MSC-CM on edematous lung injury.…”