| Research Abstract |
We examined the role of MAP kinases, critical enzymes in cell signaling, in the generation of dysplastic and hypoplastic kidney after fetal urinary tract obstruction. Urinary tract obstruction in fetal lambs at gestational day 50 produces hypoplastic kidneys whereas obstruction at day 60 generates multicystic dysplasia. Fetal pattern of MAP kinase (upregulation of activated ERK and p38 and downregulation of JNK) was observed in cyst epithelium. Activated ERK correlated both temporally and spatially with cyst formation and TGF-B expression, a marker of fibrosis, in the interstitial space. In in vitro experiments, cyclic stretch of ureteric bud cells induced activation of ERK, p38, proliferation, and TGF-B production. Blockade or ERK or p38 inhibited proliferation and TGF-B production. Apoptosis was observed at a later stage (48 hours after stretch), and suppressed by inhibitors of ERK and p38 as well as by anti-TGF-β antibody. In inner medullary collecting duct cells, a differentiated k
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idney epithelial cell line, a JNK inhibitor suppressed proliferation and the expression of E-cadherin, a marker of differentiation, and increased apoptosis and TGF-β expression, suggesting that JNK is necessary for differentiation and the maintenance of cell integrity. In kidneys obstructed at gestational day 50, apoptotic cells were not increased compared with those obstructed at day 60. On the other hand, proliferative cells were decreased which was considered to be due to the larger percentage of cystic area observed from 7 days after obstruction. Finally, inhibition of ERK attenuated cyst formation, kidney enlargement, hypertension, loss of urinary concentrating ability, and deterioration of renal function in a mouse model of polycystic kidney disease, a disease characterized by cyst formation similar to multicystic dysplasia. These results demonstrate that MAP kinase, especially ERK, plays an important role in the pathogenesis of renal anomaly due to fetal urinary tract obstruction. Less
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