PMC:3475485 / 12857-16200 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3475485","sourcedb":"PMC","sourceid":"3475485","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3475485","text":"Discussion\nAlthough remarkable progress toward understanding the genetics and pathophysiology of ADPKD has been made to date, it is still unclear how mutations in disease-causing genes trigger cystogenesis and what important role other molecules play in the cystic phenotype [12]. Our aim here was to identify genes associated with the cystic phenotype using Pkd2 KO and PKD2 TG MEF cells. In a previous study, overexpression of human PKD2 led to anomalies in tubular function, due to abnormalities in tubule morphogenesis [13]. Similar findings have been made for the PKD1 gene. For this gene, gain/loss of function and haploinsufficiency leads to cystogenesis, with the severity of the phenotype being related to the level of imbalance. More severe phenotypes are seen for gain and loss of function than for haploinsufficiency [4]. In the present study, the association between cystogenesis and the loss or gain of PKD2 supports the idea that PC2 functions through Pkd2 mutant MEF cells.\nPresently, we found Wnt4 to be up-regulated in Pkd2 KO MEF cells and down-regulated in PKD2 TG MEF cells. Wnt4, a member of the Wnt family of lipid-modified secreted glycoproteins, plays central roles in the initial stages of the tubulogenic program. Wnt4 is expressed in the pretubular aggregate, as one of the first molecular responses to inductive signaling mediated by ureteric epithelium [14].\nAQP1 was observed to be up-regulated in both Pkd2 KO and PKD2 TG MEF cells. AQP1 is a channel-forming integral membrane protein found in erythrocytes and water-transporting tissues, including the kidney, where it is localized to the proximal tubules and thin descending limbs of Henle's loop. The selective expression pattern of AQP1 in human nephrogenesis suggests that proximal tubules and thin descending limbs become permeable to water early in development. A predominantly apical expression of AQP1 is found during a critical period of the nephrogenesis, during formation of the proximal tubule, as well as in the early stage of ADPKD; in normal tubules, distribution is both apical and basolateral [15]. Another interesting defect in urine-concentrating ability was described in the Aqp1 knockout mouse. Although these mice were grossly normal in terms of survival and appearance, they were vulnerable to water deprivation and became severely dehydrated. These results suggest that AQP1 is required for the formation of concentrated urine [16].\nWe have found PKC-α and Bcl-2 associated transcription factor to be down-regulated in Pkd2 KO MEF cells and up-regulated in PKD2 TG MEF cells. Recent observations in animal models of PKD have implicated apoptosis in its pathogenesis. PKC- and Erk-dependent pathways are critical components of the cell survival by suppressing the apoptosis [17]. We also have demonstrated the role for PKD2 in cellular adhesion processes. In this study, ITGα4 was up-regulated in Pkd2 KO MEF cells and down-regulated in PKD2 TG MEF cells. It suggests that adhesion molecule such as ITGα4 may be associated with PKD2 mutation-related pathogenesis.\nIn conclusion, by using the cDNA microarray technique, we have found several candidate genes that may be involved in cystogenesis: PKCα, ITGα4 and AQP1. These genes were affected by PKD2 expression and may be related to cyst formation of kidney together with the PKD2 gene.","divisions":[{"label":"Title","span":{"begin":0,"end":10}}],"tracks":[{"project":"2_test","denotations":[{"id":"23105924-15498457-44845730","span":{"begin":276,"end":278},"obj":"15498457"},{"id":"23105924-18048422-44845731","span":{"begin":524,"end":526},"obj":"18048422"},{"id":"23105924-9568711-44845732","span":{"begin":830,"end":831},"obj":"9568711"},{"id":"23105924-17537789-44845733","span":{"begin":1384,"end":1386},"obj":"17537789"},{"id":"23105924-8760258-44845734","span":{"begin":2094,"end":2096},"obj":"8760258"},{"id":"23105924-9767520-44845735","span":{"begin":2435,"end":2437},"obj":"9767520"},{"id":"23105924-17007817-44845736","span":{"begin":2781,"end":2783},"obj":"17007817"}],"attributes":[{"subj":"23105924-15498457-44845730","pred":"source","obj":"2_test"},{"subj":"23105924-18048422-44845731","pred":"source","obj":"2_test"},{"subj":"23105924-9568711-44845732","pred":"source","obj":"2_test"},{"subj":"23105924-17537789-44845733","pred":"source","obj":"2_test"},{"subj":"23105924-8760258-44845734","pred":"source","obj":"2_test"},{"subj":"23105924-9767520-44845735","pred":"source","obj":"2_test"},{"subj":"23105924-17007817-44845736","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#c493ec","default":true}]}]}}