Podocyte hypertrophy, "adaptation," and "decompensation" associated with glomerular enlargement and glomerulosclerosis in the aging rat: Prevention by calorie restriction
Podocyte hypertrophy, "adaptation," and "decompensation" associated with glomerular enlargement and glomerulosclerosis in the aging rat: Prevention by calorie restriction
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DOI：
10.1681/asn.2005050488
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发表时间：
2005-10-01
影响因子：
13.6
通讯作者：
Wiggins, RC
中科院分区：
文献类型：
--
作者：
Wiggins, JE;Goyal, M;Wiggins, RC
在2、6、17和24月龄的Fischer 344大鼠中，评价足细胞耗竭是否会引起衰老性肾小球硬化。自由进食的大鼠在24个月时出现蛋白尿和肾小球硬化，而限制热量的大鼠则没有。没有证据表明年龄相关的肾小球足细胞线性减少，相反，自由进食的大鼠随着时间的推移出现了肾小球增大。为了适应肾小球体积的增加，足细胞主要发生肥大，而其他肾小球细胞发生增生。确定了足细胞在足细胞损失和肾小球硬化的过程中所经过的肥大阶段：第1阶段，正常足细胞;第2阶段，非应激足细胞肥大;第3阶段，“适应性”足细胞肥大，表现为结构组分（例如，结蛋白）但维持正常功能;第4阶段，相对于总肾小球体积的“失代偿”足细胞肥大表现为正常足细胞功能所必需的关键机制的产生减少（例如，肾母细胞瘤I蛋白[WT 1]、转录因子pod 1、nephrin、肾小球上皮蛋白1、足细胞标记蛋白、血管内皮生长因子和α 5 IV型胶原蛋白），并与足突增宽和滤过效率降低（蛋白尿）相关;第5阶段，足细胞数量减少，与局灶节段性肾小球硬化相关。相比之下，在热量限制的大鼠，肾小球肿大是轻微的，显着的足细胞肥大没有发生，足细胞机械是不变的，没有蛋白尿，肾小球硬化症没有发展。因此，肾小球增大与足细胞肥大相关，而不是增生。超过一定阈值的肥大与足细胞应激相关，然后失败，最终导致肾小球足细胞数量减少。这个过程可以通过限制卡路里来防止。
Whether podocyte depletion could cause the glomerulosclerosis of aging in Fischer 344 rats at ages 2, 6, 17, and 24 mo was evaluated. Ad libitum-fed rats developed proteinuria and glomerulosclerosis by 24 mo, whereas calorie-restricted rats did not. No evidence of age-associated progressive linear loss of podocytes from glomeruli was found. Rather, ad libitum-fed rats developed glomerular enlargement over time. To accommodate the increased glomerular volume, podocytes principally underwent hypertrophy, whereas other glomerular cells underwent hyperplasia. Stages of hypertrophy through which podocytes pass en route to podocyte loss and glomerulosclerosis were identified: Stage 1, normal podocyte; stage 2, nonstressed podocyte hypertrophy; stage 3, "adaptive" podocyte hypertrophy manifest by changes in synthesis of structural components (e.g., desmin) but maintenance of normal function; stage 4, "decompensated" podocyte hypertrophy relative to total glomerular volume manifest by reduced production of key machinery necessary for normal podocyte function (e.g., Wilms' tumor I protein [WT1], transcription factor pod1, nephrin, glomerular epithelial protein 1, podocalyxin, vascular endothelial growth factor, and alpha 5 type IV collagen) and associated with widened foot processes and decreased filter efficiency (proteinuria); and stage 5, podocyte numbers decrease in association with focal segmental glomerulosclerosis. In contrast, in calorie-restricted rats, glomerular enlargement was minor, significant podocyte hypertrophy did not occur, podocyte machinery was unchanged, there was no proteinuria, and glomerulosclerosis did not develop. Glomerular enlargement therefore was associated with podocyte hypertrophy rather than hyperplasia. Hypertrophy above a certain threshold was associated with podocyte stress and then failure, culminating in reduced podocyte numbers in sclerotic glomeruli. This process could be prevented by calorie restriction.