Podocyte Hypertrophy, “Adaptation,” and “Decompensation” Associated with Glomerular Enlargement and Glomerulosclerosis in the Aging Rat

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 1 protein [WT1], transcription factor pod1, nephrin, glomerular epithelial protein 1, podocalyxin, vascular endothelial growth factor, and alpha5 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.