title: Neutrophil gelatinase-associated lipocalin suppresses cyst growth by Pkd1 null cells in vitro and in vivo.
abstract: Cyst growth in patients with autosomal dominant polycystic kidney disease is thought to be due to increased tubular cell proliferation. One model to explain this altered proliferation suggests that the polycystin proteins PC1 and PC2 localize to apical cilia and serve as an integral part of the flow-sensing pathway thus modulating the proliferative response. We measured proliferation and apoptosis in proximal tubule derived cell lines lacking PC1. These cells showed increased rates of proliferation, a decreased rate of apoptosis, compared to control heterozygous cell lines, and spontaneously formed cysts rather than tubules in an in vitro tubulogenesis assay. Addition of neutrophil gelatinase associated lipocalin (NGAL), a small secreted protein that binds diverse ligands, to the cells lacking PC1 inhibited proliferation and increased apoptosis leading to slower cyst growth in vitro. Sustained over-expression at low level of NGAL by an adenoviral delivery system suppressed cyst enlargement without improving renal function in the Pkd1 mutant mice. Our studies show that renal epithelial cells lacking PC1 have an inherent tendency to hyper-proliferate forming cysts in vitro independent of a flow stimulus. The potential benefit of attenuating cyst growth with NGAL remains to be determined.
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Karihaloo
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marlier
authors.affiliation: Section of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Sekiya
authors.initials: S
authors.lastname: Shibazaki
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
mesh_terms: D000209:Acute-Phase Proteins / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003560:Cysts / Q000209:etiology / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000502:physiology*; D051379:Mice; D015513:Oncogene Proteins / Q000502:physiology*; D007690:Polycystic Kidney Diseases; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D050396:TRPP Cation Channels / Q000172:deficiency / Q000502:physiology*
chemical_list: D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D050396:TRPP Cation Channels; C071332:Lcn2 protein, mouse