Abstract
Polycystic kidney disease (PKD) is a genetic disorder characterized by fluid-filled cysts in the kidney and liver that ultimately leads to end-stage renal disease. Currently there is no globally approved therapy for PKD. The Notch signaling pathway regulates cellular processes such as proliferation and de-differentiation, which are cellular hallmarks of PKD. Thus we hypothesized that the Notch pathway plays a critical role in PKD. Evaluation of protein expression of Notch signaling components in kidneys of Autosomal Recessive PKD (ARPKD) and Autosomal Dominant PKD (ADPKD) mouse models and of ADPKD patients revealed that Notch pathway members, particularly Notch3, were consistently upregulated or activated in cyst-lining epithelial cells. Notch3 expression correlated with rapidly growing cysts and co-localized with the proliferation marker, PCNA. Importantly, Notch inhibition significantly decreased forskolin-induced Notch3 activation and proliferation of primary human ADPKD cells, and significantly reduced cyst formation and growth of human ADPKD cells cultured in collagen gels. Thus our data indicate that Notch3 is aberrantly activated and facilitates epithelial cell proliferation in PKD, and that inhibition of Notch signaling may prevent cyst formation and growth.
Highlights
(N3) or Notch[4] (N4)
To determine whether Notch signaling is modulated in Polycystic kidney disease (PKD), we examined protein expression of Notch pathway members in various mouse models of PKD
The cpk mutant is a well-studied model of Autosomal Recessive PKD (ARPKD). cpk mice harbor a homozygous mutation in cys[1], which encodes the cilia-associated protein, cystin, and exhibit rapidly-progressing cystic disease that leads to renal failure and death typically by 3 weeks of age[22,23,24]
Summary
Binding of ligand to a receptor results in a series of proteolytic cleavage events initiated by presenilin-dependent gamma secretase-like proteases. This releases the Notch receptor intracellular domain (NICD), which translocates into the nucleus. Notch signaling is upregulated in mature podocytes and tubular cells in diabetic nephropathy and many other kidney diseases[17,18]. A direct role of the Notch signaling pathway in PKD has not been shown in mammals. We sought to determine the expression pattern and contribution of Notch signaling pathway components in PKD, using both ARPKD and ADPKD mouse models and ADPKD patient samples. Inhibition of Notch signaling using gamma secretase inhibitors resulted in decreased proliferation and attenuation of cyst progression in vitro
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