| Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic human disorders, is characterized by the formation and progressive expansion of multiple cystic lesions, which compromise the function of normal renal parenchyma and lead to nearly 10% of cases of end-stage renal failure in adults. It is identified that mutations in three different genes, PKD1, PKD2 and PKD3 cause almost all cases of ADPKD. Throughout the course of these diseases, renal tubular function and structure are altered, changing the normal microenvironment of all the renal cells resulted from the protein products of the mutated genes. Of the three potential causes of the formation and progressive expansion of cystic lesions, downstream obstruction, compositional changes in extracellular matrix, and proliferation of partially dedifferentiated cells evidence strongly supports the latter as the primary abnormality. The accumulated experiments confirm that a single cyst is derived from the proliferation of one tubular epithelial cell. ADPKD cyst-lining epitherial cell cultured in vitro then appears to be an ideal cell model to further investigate the pathogenesis and treatment of ADPKD. The expanding body of information indicates that growth factors are involved in renal cystogenesis and progress. Keratinocyte growth factor (KGF) is a member of the rapidly growing fibroblast growth factor (FGF) family with a distinctive pattern of target-cell specificity. Studies performed in cell culture suggested that KGF was mitogenically active only on epithelial cells, albeit from a variety of tissues. It has been demonstrated that KGF stimulates proliferation and migration of these cells, affects differentiation processes, mediates mesenchymal-epithelial interactions and promotes morphogenesis. Furthermore, recent studies have demonstrated a protective function of this growth factor in vitro and in vivo. Relatively little is known thus far about action of KGF on pathogenesis of ADPKD. Therefore the current studies were designed to observe the expression of KGF and its receptor (KGFR) in ADPKD cystic tissues on protein level and to investigate the proliferation and extracellular matrix synthesis of KGF on ADPKD cyst-lining epithelial cells in cellular level, compared with those of normal kidney tissues and LLC-PK1 cells respectively. There were several conclusions demonstrated.1. Overexpression of KGF protein and its receptor in ADPKD cystic tissues with an autocrine pattern was detected by the method of western blotting and immunochemistry. The increased local expression of KGF and KGFR proteins might have implication for ADPKD. 2. It was revealed by the results of MTT, assessment of cell cycle and histological appearance that proliferation of ADPKD cyst-lining epithelial cells and LLC-PK1 cells in a dose- and time-dependent manner was significantly stimulated by administration of KGF. Compared with that of LLC-PK1 cells, a remarkable response to KGF was induced in ADPKD cyst-lining epithelial cells. 3. Signaling pathway mediated by the activation of Ras-MAPK is the mechanism responsible for the proliferative effect of KGF on both ADPKD cyst-lining epithelial cells and LLC-PK1 cells, which was demonstrated by western blotting and c-jun and c-fos immunocytochemistry.4. With the examination of ELISA, the increasing synthesis of type IV collagen and LN was greatly discovered after ADPKD cyst-lining epithelial cells exposure to KGF, suggesting that ADPKD cyst-lining epithelial cells might be involved in the abnormal changes of composition and structure in ECM. Interestingly, the similar results were not produced in LLC-PK1 cells.The evidence resulted from DNA integrity analyzed by flow cytometry and the morphological abnormalities observed with the transmission electron microscopy demonstrated that apoptosis of the5. KGF-treated LLC-PK1 cells was present. It was speculated that apoptosis might be an important means to resolve KGF-induced LLC-PK1 cells hyperplasis. Alternatively this phenomen...
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