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 (mean±SEM: 3.3±0.1µm before injury versus 12.5±0.2µm 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±0.4µm2in control versus 24.1±0.6µm2at 10 days;P<0.01 and 24.6±0.6µm2at 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.
Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts; humphreysbd@wustl.edu rkramann@gmx.net.|Division of Nephrology and Clinical Immunology, RWTH Aachen University Medical Faculty, RWTH Aachen University, Aachen, Germany.
Rafael
R
Kramann
Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; and.|Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Janewit
J
Wongboonsin
Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; and.
Monica
M
Chang-Panesso
Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; and.
Flavia G
FG
Machado
Division of Nephrology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; and humphreysbd@wustl.edu rkramann@gmx.net.
Benjamin D
BD
Humphreys
D000818:Animals; D002196:Capillaries / Q000503:physiopathology*; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051379:Mice; D020286:Pericytes / Q000378:metabolism / Q000473:pathology*; D012039:Regional Blood Flow; D000071676:Zinc Finger Protein GLI1 / Q000096:biosynthesis
C498520:Gli1 protein, mouse; D000071676:Zinc Finger Protein GLI1
AKI; CKD; capillary; pericyte