Gli1⁺ pericyte loss induces capillary rarefaction and proximal tubular injury

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-CreERt2; R26tdTomato reporter mice, we observed increased distance between Gli1⁺ pericytes and endothelial cells after AKI (mean6 SEM: 3.360.1 mm before injury versus 12.560.2 mm after injury; P,0.001). Using a genetic ablationmodel, 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 (mean6SEM capillaries/high-power field: 67.664.7 in control versus 44.164.8 at 56 days; P,0.05) and increasedcross-sectional area (mean6 SEM: 21.960.4 mm2 in control versus 24.160.6 mm2 at 10 days; P,0.01 and 24.66 0.6 μm² 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 fromcapillaries, and that pericyte loss is sufficient to trigger transient tubular injury and permanent peritubular capillary rarefaction.