2005 Fiscal Year Final Research Report Summary
Study of renal diseases caused by podocyte injury
| Project/Area Number |
15209030
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | Tokai University |
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Principal Investigator |
MATSUSAKA Taiji Tokai University, Institute of Medical Sciences, Associate Professor, 総合医学研究所, 助教授 (50317749)
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| Co-Investigator(Kenkyū-buntansha) |
ICHIKAWA Iekuni Tokai University, School of Medicine, Professor, 医学部, 教授 (80317768)
NIIMURA Fumio Tokai University, School of Medicine, Assistant Professor, 医学部, 講師 (30282750)
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| Project Period (FY) |
2003 – 2005
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| Keywords | podocyte / glomerular sclerosis / transgenic mice / HIV-1 associated nephropathy / angiotensin / chronic renal failure / actinin |
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| Research Abstract |
To investigate causal relationship between podocyte injury and glomerular sclerosis, a hallmark of chronic renal failure, we developed a transgenic mouse line (NEP25) in which podocyte-selective injury can be induced by a single injection of immunotoxin (LMB2). After LMB2 injection, NEP25 mice manifested injury of podocytes and other glomerular cells and rapidly developed glomerular sclerosis. Labeling of the podocyte-lineage utilizing the Cre-loxP system revealed that following downregulation of podocyte markers, podocytes were progressively lost, without transforming into other types of cell. Studies using chimeric mice revealed that injury initiated in a portion of podocytes was spread to other podocytes, thus forming a vicious cycle of self-perpetuating injury.
Using other transgenic mouse lines that we developed, we demonstrated that in the presence of FVB/N genetic background, HIV-1 genes, vpr and nef, synergistically damage podocytes, leading to collapsing FSGS similar to HIV-1 associated nephropathy of humans.
In both NEP25 and HIV-1 models, damage of podocytes was prevented remarkably by ureteral obstruction, indicating that continued glomerular filtration is a prerequisite for progressive injury of podocytes, and subsequent development of glomerular sclerosis.
We also studied the role of mutant α-Actinin-4, which causes autosomal dominant focal segmental glomerular sclerosis (FSGS) in humans. Transgenic mice expressing mutant α-Actinin-4 in podocytes developed slowly progressive FSGS. By crossing α-Actinin-4 with NEP25 mice, we demonstrated that mutant α-Actinin-4 attenuated glomerular damage induced by LMB2.
Thus, we demonstrated that in the presence of glomerular filtration, podocyte damage induced by various factors is automatically spread to other podocytes and types of cell within the glomerulus, which leads to glomerular sclerosis.
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