Expression of Neutrophil Gelatinase-associated Lipocalin Regulates Epithelial Morphogenesis in Vitro

Abstract

Growth factors such as hepatocyte growth factor (HGF) are highly up-regulated during development and following renal injury and are known to induce marked morphogenic actions in cultured tubular epithelial cells, including scattering, migration, single cell branching morphogenesis, and multicellular branching tubulogenesis. In the present study, we demonstrate that HGF stimulates epithelial cells to express neutrophil gelatinase-associated lipocalin (Ngal), a member of the lipocalin family of secreted proteins that has recently been shown to participate in mesenchymal-epithelial transformation via its ability to augment cellular iron uptake. At concentrations below those found to mediate iron transport, purified Ngal can induce a promigratory and probranching effect that is dependent on ERK activation. The suppression of Ngal expression using short hairpin RNA results in increased cyst formation by tubular cells. However, the simultaneous addition of Ngal and HGF leads to direct association of the two proteins, and results in a partial inhibition of HGF-mediated activation of c-Met and the downstream MAPK and phosphatidylinositol 3-kinase signaling pathways. This inhibitory effect down-regulates HGF-stimulated single cell migration, and limits branching morphogenesis at both the single cell and multicellular level. These experiments demonstrate that the local expression of Ngal can play a regulatory role in epithelial morphogenesis by promoting the organization of cells into tubular structures while simultaneously negatively modulating the branching effects of HGF.

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

“…lcn2 was an endogenous epithelial inducer (Yang et al, 2002) and stimulated the epithelial phenotype of transformed cells (Hanai et al, 2005;. lcn2 also promoted tubulogenesis by regulating epithelial morphogenesis (Gwira et al, 2005). Although the role of lcn2 as an epithelial inducer as related to the effects of lcn2 on the astrocyte morphology found in the present study is not currently understood, it is evident that lcn2 has an important role in determining cellular morphology.…”

Creatine pretreatment prevents birth asphyxia–induced injury of the newborn spiny mouse kidney

“…The increased areas of interstitium may indicate a failure or delay of the loops of the outer, most immature cortical glomeruli to continue to lengthen and extend into the medulla. Of note, under suboptimal conditions, Ngal can facilitate tubular development and maturation through its iron binding capacity and regulation of genes involved in mesenchymal-epithelial transition (21)(22)(23). This developmental role of Ngal was suggested by La Manna et al, as a possible reason for increased urinary Ngal concentrations in very low birth weight preterm infants with impaired renal function (24).…”

Urinary NGAL Marks Cystic Disease in HIV-Associated Nephropathy

“…We first identified NGAL as a tubulogenic factor, 22 a property supported by studies in cell lines. 23 Likewise, in adult kidney, 14 thyroid cells, 24 and gastric epithelia, 25 NGAL acts as a growth factor, whereas in other cells, such as polycystickidney-disease-related renal cysts, NGAL may serve as a proapoptotic factor. 26 A common growth mechanism may underlie these phenomena, perhaps with iron loaded NGAL, 22,24 but exact mechanisms are unclear.…”