Reducing mTOR Augments Parietal Epithelial Cell Density in a Model of Acute Podocyte Depletion and in Aged Kidneys.

Publication Type:

Journal Article

Source:

American journal of physiology. Renal physiology, p.ajprenal.00196.2016 (2016)

Abstract:

Parietal epithelial cells (PEC) response to glomerular injury may underlie a common pathway driving fibrogenesis following podocyte loss that typifies several glomerular disorders. Although the mammalian target of rapamycin (mTOR) pathway is important in cell homeostasis, little is known of the biological role or impact of reducing mTOR activity on PECs response following podocyte depletion, nor in the aging kidney. The purpose of these studies was to determine the impact on PECs of reducing mTOR activity following abrupt experimental depletion in podocyte number, as well as in a model of chronic podocyte loss and sclerosis associated with aging. Podocyte depletion was induced by an anti-podocyte antibody and rapamycin started at D5 until sacrifice at D14. Reducing mTOR did not lead to a greater reduction in podocyte density despite greater glomerulosclerosis. However, mTOR inhibition lead to an increase in PEC density and PEC derived crescent formation. Additionally, markers of epithelial to mesenchymal transition (PDGFβR, α-SMA, Notch 3) and PEC activation (CD44, Collagen IV) were further increased by mTOR reduction. Aged mice treated with rapamycin for 1, 2 and 10-week before sacrifice at 26.5 months (≈75 year old human age) had increased number of glomeruli with a crescentic appearance. mTOR inhibition either at a high or low levels lead to changes in PEC phenotype indicating PEC morphology is sensitive to changes mediated by global mTOR inhibition.