| Project/Area Number |
17590840
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Jichi Medical University |
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Principal Investigator |
MUTO Shigeaki Jichi Medical University, School of Medicine, Nephrology, Associate Professor, 医学部, 助教授 (40190855)
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| Co-Investigator(Kenkyū-buntansha) |
MIYATA Yukio Jichi Medical University, School of Medicine, Nephrology, Visiting Researcher, 医学部, 客員研究員 (00285777)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | tight junction / claudin-2 / proximal tubule / Na / Cl transport |
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| Research Abstract |
Claudin-2 is highly expressed in tight junctions of mouse proximal tubule composing of a leaky epithelium with unique paracellular permeability properties that underlies its high rate of NaCl reabsorption. To investigate the functional role of claudin-2 in the paracellular NaCl transport in this nephron segment, we generated mice lacking claudin-2 [Cld2^<-/->] by gene targeting disruption and compared their morphological and functional properties with their wild-type littermates [Cld2^<+/+>]. The Cld2^<-/-> mice had grossly normal appearance, activity, growth, and behavior. Light microscopic findings exhibited no gross histological abnormalities in the Cld2^<-/-> kidney. Ultrathin section and freeze-fracture replica electron microscopy revealed that, similar to Cld2^<+/+> mice, the proximal tubule of Cld2^<-/-> mice was characterized by poorly-developed tight junctions with one or two continuous strands. In sharp contrast, the functional studies in isolated perfused S2 segments of proximal tubules showed that net transepithelial absorptions of Na^+, Cl^-, and water were significantly decreased in Cld2^<-/-> mice and that the claudin-2-deficiency led to an increase in paracellular shunt resistance without affecting apical or basolateral membrane resistances. Moreover, the Na^+-selectivity of paracellular permeability of proximal tubules in Cld2^<+/+> mice was converted to be Cl^--selective in Cld2^<-/-> mice. Cld2^<-/-> mice intravenously given 2% NaCl exhibited exaggerated urinary NaCl loss compared with Cld2^<+/+> mice, although Cld2^<-/-> mice under free access to water and food showed urinary excretions of NaCl with a similar magnitude to Cld2^<+/+> mice. We conclude that claudin-2 constitutes leaky and Na^+-selective paracellular channels within tight junctions of mouse proximal tubule.
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