Polycystic kidney disease (PKD) is one of the most common inherited diseases and is characterized by the development of fluid-filled
cysts along multiple segments of the nephron.
Autosomal dominant polycystic kidney disease (
ADPKD) is the most common form of PKD, which is caused by mutations in either PKD1 or PKD2 genes that encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. As
ADPKD progresses,
cysts enlarge and disrupt normal kidney architecture, eventually leading to
kidney failure. Our previous study showed that overexpression of exogenous kidney-specific
neutrophil gelatinase-associated lipocalin (NGAL) reduced
cyst progression and prolonged the lifespan of
ADPKD mice (Pkd1L3/L3, 2L3 for short). In this study, we attempted to explore the underlying mechanism of reduced
cyst progression in the presence of NGAL using immortalized 2L3 cells. The results of MTT and
BrdU incorporation assays showed that recombinant mouse NGAL (mNGAL)
protein significantly decreased the viability and proliferation of 2L3 cells. Flow cytometry and western blot analyses showed that mNGAL inhibited activation of the ERK and AKT pathways and induced apoptosis and autophagy in 2L3 cells. In addition, a 3D cell culture platform was established to identify
cyst progression in 2L3 cells and showed that mNGAL significantly inhibited
cyst enlargement in 2L3 cells. Overexpression of secreted mNGAL (pN + LS) and nonsecreted mNGAL (pN - LS) repressed cell proliferation and
cyst enlargement in 2L3 cells and had effects on markers involved in proliferation, apoptosis, and autophagy. However, secreted mNGAL had a more pronounced and consistent effect than that of nonsecreted form. These results reveal that secreted mNGAL has stronger ability to inhibit
cyst enlargement of
ADPKD cells than that of nonsecreted form. These findings could help to identify strategies for the future clinical treatment of
ADPKD.