Gli1+ pericyte loss induces capillary rarefaction and proximal tubular injury

R Kramann, J Wongboonsin… - Journal of the …, 2017 - journals.lww.com
R Kramann, J Wongboonsin, M Chang-Panesso, FG Machado, BD Humphreys
Journal of the American Society of Nephrology, 2017journals.lww.com
Peritubular capillary rarefaction is hypothesized to contribute to the increased risk of future
CKD after AKI. Here, we directly tested the role of Gli1+ kidney pericytes in the maintenance
of peritubular capillary health, and the consequences of pericyte loss during injury. Using
bigenic Gli1-CreER t2; R26tdTomato reporter mice, we observed increased distance
between Gli1+ pericytes and endothelial cells after AKI (mean±SEM: 3.3±0.1 µm before
injury versus 12.5±0.2 µm after injury; P< 0.001). Using a genetic ablation model, we asked …
Abstract
Peritubular capillary rarefaction is hypothesized to contribute to the increased risk of future CKD after AKI. Here, we directly tested the role of Gli1+ kidney pericytes in the maintenance of peritubular capillary health, and the consequences of pericyte loss during injury. Using bigenic Gli1-CreER t2; R26tdTomato reporter mice, we observed increased distance between Gli1+ pericytes and endothelial cells after AKI (mean±SEM: 3.3±0.1 µm before injury versus 12.5±0.2 µm after injury; P< 0.001). Using a genetic ablation model, we asked whether pericyte loss alone is sufficient for capillary destabilization. Ten days after pericyte ablation, we observed endothelial cell damage by electron microscopy. Furthermore, pericyte loss led to significantly reduced capillary number at later time points (mean±SEM capillaries/high-power field: 67.6±4.7 in control versus 44.1±4.8 at 56 days; P< 0.05) and increased cross-sectional area (mean±SEM: 21.9±0.4 µm 2 in control versus 24.1±0.6 µm 2 at 10 days; P< 0.01 and 24.6±0.6 µm 2 at 56 days; P< 0.001). Pericyte ablation also led to hypoxic focal and subclinical tubular injury, reflected by transient expression of Kim1 and vimentin in scattered proximal tubule segments. This analysis provides direct evidence that AKI causes pericyte detachment from capillaries, and that pericyte loss is sufficient to trigger transient tubular injury and permanent peritubular capillary rarefaction.
Lippincott Williams & Wilkins