Abstract
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.
Highlights
Polycystic kidney disease (PKD), one of the most common inherited diseases, is characterized by the development of fluid-filled cysts along multiple segments of the nephron [1].Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of PKD, which is an adult-onset PKD for which most patients do not develop symptoms until they are in their forties [2]
We found that overexpression of neutrophil gelatinase-associated lipocalin (NGAL) in an ADPKD mouse model (Pkd1L3/L3 × NGALTg/Tg mice) reduced cyst progression and prolonged the lifespan of Pkd1L3/L3 mice, accompanied by changes in a series of molecular pathways involved in proliferation, apoptosis and fibrosis [31]
The Pkd1L3/L3 (2L3) cell line was established by SV40 virus transduction of primary renal epithelial cells from 2L3 mice, an ADPKD mouse model, to induce an immortalized cell line [17,18]
Summary
Polycystic kidney disease (PKD), one of the most common inherited diseases, is characterized by the development of fluid-filled cysts along multiple segments of the nephron [1]. ADPKD is the most common form of PKD, which is an adult-onset PKD for which most patients do not develop symptoms until they are in their forties [2]. ADPKD is the result of mutations in either PKD1 (85%) or PKD2 (15%) genes that encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively [3,4]. As ADPKD progresses, cysts enlarge and disrupt normal kidney architecture, eventually leading to kidney failure. The mechanism involved in ADPKD is complicated and remains to be explored. Functional loss of PC1 and/or PC2 in ADPKD leads to reduced intracellular calcium concentrations, alleviating calcium-sensitive adenylyl cyclase (AC)
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