| Project/Area Number |
17590825
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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 | Nagoya University |
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Principal Investigator |
YUZAWA Yukio Nagoya University, Graduate School of Medicine, Assistant Professor, 大学院医学系研究科, 講師 (00191479)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUO Seiichi Nagoya University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (70190410)
NIKI Ichiro Oita University, School of Medicine, Professor, 医学部, 教授 (10262908)
KADOMATSU Kenji Nagoya University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (80204519)
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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 |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | diabetic nephropathy / midkine / protein kinase C / ERK / calmodulin / VEGF / eNOS / endothelial injury / VGF / exudative lesion / nodular lesion / diabetic nephropathy / Midkine / MAPK / PKC / chemokine / hilar hyalinosis |
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| Research Abstract |
We characterized the pathogenesis of two interesting mice models for diabetic nephropathy ; i.e., 1) Streptozotocin (STZ)-treated diabetic model in midkine (Mdk)+/+ mice (129/SV background), and 2) β3 cell-specific calmodulin overexpressing mice (CaMTg mice).
First, mice deficient in the growth factor midkine (Mdk-/-) exhibited strikingly milder nephropathy, even though Mdk-/- and +/+ mice showed similar extents of hyperglycemia after STZ injection. MK expression was induced in the glomerular mesangium of Mdk+/+ mice with diabetic nephropathy, and in primary cultured mesangial cells exposed to high glucose. Mdk-/- mesangial cells exhibited reduced phosphorylation of protein kinase C and extracellular signal-regulated kinase, and reduced production of transforming growth factor-β_1 upon high glucose loading. Exogenous MK restored extracellular signal-regulated kinase phosphorylation in Mdk-/- cells under high glucose conditions, whereas a MK antisense oligonucleotide suppressed it in Mdk
… More
+/+ cells. This suggests that MK accelerates the intracellular signaling network evoked by hyperglycemia in nephropathy.
Second, CaMTg mice showed evident albuminuria at 3 months of age and thereafter. Nodular lesions were seen in CaMTg mice at 6 and 9 months of age, and even exudative lesions occasionally appeared in 9 month-old CaMTg mice. Hyalinosis of the afferent and efferent arterioles was observed in 6- and 9-month-old CaMTg. The expression level of endothelial nitric oxidase synthase (eNOS) was decreased and that of VEGF, mainly distributed in the podocytes, was elevated in the 3- and 6-month-old CaMTg kidney. VEGF receptor (VEGFR)-1 was less expressed in the 6M CaMTg kidney than nTg one. Such difference between the CaMTg and nTg kidneys was not seen for VEGFR-2. There was an increase of the thrombomodulin-positive vascular area in the 6- and 9-month-old CaMTg mice compared to the nTg ones. These findings indicate CaMTg mice developed most typical distinct lesions of human diabetic nephropathy. The elevated VEGF level and diminished eNOS and VEGFR-1 expression may result in preferential activation of the VEGFR-2 signaling and eventual proliferation of the endotherial cells.
We propose these models are very useful for investigations of the pathogenesis of diabetic nephropathy and for the development of new treatments. Less
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