2006 Fiscal Year Final Research Report Summary
Glomerular podocyte injury in lifestyle-related disease : elucidation of its mechanism and establishment of novel therapeutic strategy to inhibit proteinuria
| Project/Area Number |
17590820
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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 | The University of Tokyo |
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Principal Investigator |
NAGASE Miki The University of Tokyo, Faculty of Medicine, Visiting Research Associate, 医学部附属病院, 寄付講座教員 (60302733)
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| Co-Investigator(Kenkyū-buntansha) |
KANAME Shinya The University of Tokyo, Faculty of Medicine, Visiting Associate Professor, 医学部附属病院, 客員助教授 (60224581)
GOTODA Takanari The University of Tokyo, Faculty of Medicine, Visiting Associate Professor, 医学部附属病院, 客員助教授 (60322731)
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| Project Period (FY) |
2005 – 2006
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| Keywords | podocyte injury / proteinuria / glomerulosclerosis / chronic kidney disease / metabolic syndrome / aldosterone / oxidative stress / adipocytokines |
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| Research Abstract |
In this study, we demonstrated the involvement of podocyte injury in the pathogenesis of proteinuria and glomerulosclerosis in Dahl salt hypertensive rats, which were effectively ameliorated by selective aldosterone blocker eplerenone. Aldosterone-infused rats fed a high salt diet demonstrated podocyte injury and massive proteinuria, which was completely reversed by eplerenone. Reduction of systemic blood pressure by hydralazine failed to prevent podocyte injury and proteinuria, whereas antioxidant tempol reduced the injury. Mineralocorticoid receptor was detected in the podocytes in vivo and in vitro, and aldosterone caused induction of its effector kinase Sgk1, activation of NADPH oxidase and generation of reactive oxygen species. We also demonstrated enhanced proteinuria and podocyte injury in metabolic syndrome model SHR/NDmcr-cp (SHR/cp) compared with non-obese SHR. Serum aldosterone level and renal Sgk1 expression were elevated in SHR/cp. Eplerenone as well as tempol effectively improved podocyte damage and proteinuria. As for the mechanisms of aldosterone excess, visceral adipocytes isolated from SHR/cp secreted substances that stimulate aldosterone production in adrenocortical cells. Adipocytes from non-obese SHR did not show such activity. Our data suggest that adipocyte-derived factors might contribute to the aldosterone excess, podocyte injury, and proteinuria in this model. Recent studies indicated that podocyte injury plays a pathogenetic role also in diabetic, hypertensive, and obesity-related glomerulopathy. Thus, aldosterone blockage can be an excellent therapeutic strategy for the treatment of podocyte injury, proteinuria, cardiovascular and renal complications in these conditions. We also demonstrated the protective actions of statins and adrenomedullin against podocyte injury.
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