Autosomal dominant polycystic kidney disease (ADPKD) is a hyperplastic disorder in which aberrant growth of tubule epithelial cells causes the formation of numerous fluid-filled cysts, massively enlarged kidneys and progressive loss of renal function. Although cysts are benign neoplasms, they ultimately cause renal insufficiency through extensive nephron loss and replacement of adjacent parenchyma with fibrosis. The mechanisms by which cysts destroy the kidneys are poorly understood;however changes in the deposition of the extracellular matrix (ECM) are likely to be important. In a microarray analysis of cultured human ADPKD cyst epithelial cells, periostin mRNA was over expressed 15-fold compared to normal human kidney (NHK) cells. Periostin, initially identified in osteoblasts as a soluble ECM molecule, is not expressed in normal adult kidneys but is expressed transiently during renal development within the nephrogenic zone, a site of nephron formation and vascularization. In ADPKD, periostin was expressed in cyst-lining cells in situ, in extracellular matrix adjacent to the cysts and within cyst fluid. Expression of aV-integrin, a receptor for periostin, was 9-fold higher in ADPKD cells compared to NHK cells, and antibodies that block aV-integrin inhibited periostin-induced cell proliferation. By contrast, periostin did not affect the proliferation of normal kidney cells. We found that periostin activates integrin-linked kinase (ILK), a kinase that regulates cell proliferation and survival through activation of Akt, GSK-32/2-catenin and mTOR signaling pathways. In preliminary data, we found that periostin expression was elevated in the kidneys of pcy/pcy and Pkd2WS25/- mice, models of human PKD;and that genetic knockout of periostin (PN-/-) reduced kidney weight (as a % of body weight) in the pcy/pcy mouse. We also found that periostin levels were elevated sera of non-azotemic ADPKD patients (n = 14) compared to normal volunteers (n = 8), suggesting that periostin may be an early indicator of PKD progression. Our general hypothesis is that periostin is a novel autocrine mitogen with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD.
ADPKD is the most frequently inherited kidney disorder with a gene frequency of 1 in 500 to 1,000 births and accounts for approximately 5-9% of all end-stage renal diseases. Costs for renal transplantation, dialysis and related treatments for PKD approach $2 billion/yr in the US alone and it is estimated that by the end of this decade treatments will cost $90 billion/yr worldwide. Completion of the proposed studies will provide new information on the role of periostin, a novel autocrine mitogen secreted by mural epithelial cells with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD.
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