Renal progenitor cells revert LPS‐induced endothelial‐to‐mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides

ABSTRACT Endothelial dysfunction is a hallmark of LPS‐induced acute kidney injury (AKI). Endothelial cells (ECs) acquired a fibroblast‐like phenotype and contributed to myofibroblast generation through the endothelial‐to‐mesenchymal transition (EndMT) process. Of note, human adult renal stem/progenitor cells (ARPCs) enhance the tubular regenerative mechanism during AKI but little is known about their effects on ECs. Following LPS exposure, ECs proliferated, decreased EC markers CD31 and vascular endothelial Cadherin, and up‐regulated myofibroblast markers, collagen I, and vimentin. The coculture with ARPCs normalized the EC proliferation rate and abrogated the LPS‐induced EndMT. The gene expression analysis showed that most of the genes modulated in LPS‐stimulated ARPCs belong to cell activation and defense response pathways. We showed that the ARPC‐specific antifibrotic effect is exerted by the secretion of CXCL6, SAA4, and BPIFA2 produced after the anaphylatoxin stimulation. Next, we investigated the molecular signaling that underlies the ARPC protective mechanism and found that renal progenitors diverge from differentiated tubular cells and ECs in myeloid differentiation primary response 88–independent pathway activation. Finally, in a swine model of LPS‐induced AKI, we observed that activated ARPCs secreted CXCL6, SAA4, and BPIFA2 as a defense response. These data open new perspectives on the treatment of both sepsis‐ and endotoxemia‐induced AKI, suggesting an underestimated role of ARPCs in preventing endothelial dysfunction and novel strategies to protect the endothelial compartment and promote kidney repair.—Sallustio, F., Stasi, A., Curci, C., Divella, C., Picerno, A., Franzin, R., De Palma, G., Rutigliano, M., Lucarelli, G., Battaglia, M., Staffieri, F., Crovace, A., Pertosa, G. B., Castellano, G., Gallone, A., Gesualdo, L. Renal progenitor cells revert LPS‐induced endothelial‐to‐mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides. FASEB J. 33, 10753–10766 (2019). www.fasebj.org