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Fig. 7 | Cell Communication and Signaling

Fig. 7

From: Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection

Fig. 7

Model of the effects of osmolarity, Wnt/β-catenin, and TLR-4 signaling on the expression of the Lcn2-R and its ligand Lcn2 in IMCD cells of the kidney. a Under physiological conditions and high interstitial osmolarity, Wnt/β-catenin signaling is activated which leads to downregulation of Lcn2 and upregulation of the Lcn2-R. The latter binds proteins in the primary urine with high affinity that are degraded in lysosomes, possibly to generate adaptive osmolytes. b Bacterial infection in an initially hyperosmotic environment induces TLR-4 signaling that counteracts Wnt/β-catenin signaling, leading to disinhibition of Lcn2 expression and secretion. Urinary Lcn2 displaces proteins from the Lcn2-R as long as it is expressed in the apical membrane, and Lcn2 endocytosis leads to death of IMCD cells. c Prolonged bacterial infection amplifies TLR-4 signaling and (apo-)Lcn2 secretion to combat UTI by binding bacterial siderophores and excretion of holo-Lcn2 into the urine along with proteins. Cell death leads to inflammation and a decrease of interstitial osmolarity, which downregulates Wnt/β-catenin signaling, further amplifying Lcn2 expression and secretion while downregulating Lcn2-R expression. Lcn2-R that may still be present in the luminal membrane may take up siderophore-bound holo-Lcn2 to prevent cell death and contribute to epithelial regeneration. For further details, see “Results” and “Discussion”. The thickness of the arrows reflects the strength of gene expression, activity and/or signaling pathways. Dotted lines and shading indicate weak expression and/or signals. Question marks indicate putative mechanisms that have not been tested in this study and are addressed in the discussion. Lcn2 = lipocalin-2; a-Lcn2 = apo-Lcn2; h-Lcn2 = holo-Lcn2; Lcn2-R = lipocalin-2 receptor; IMCD = inner medullary collecting duct; UTI = urinary tract infection; UPEC = uropathogenic E- coli; LPS = lipopolysaccharide; TLR-4 = Toll-like receptor-4.

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