The Study of Kidney Microvascular Injury and Repair

Abstract

Thrombotic microangiopathies are group of diseases that refer to clinical and pathological syndromes where endothelial injury results in the manifestations of capillary thrombosis, microangiopathic hemolytic anemia, schistocytosis, and can lead to renal failure. In this thesis we aimed to study glomerular endothelial cell (GEC) injury and repair. We developed an animal model of GEC-specific injury that is based on the binding specificity of MOA lectin to the carbohydrate epitope expressed in the mouse renal microvasculature. The lectin was conjugated to saporin to enhance the killing activity. The lectin-saporin (L-S) caused a uniform and reproducible GEC injury that captured many features frequently observed in TMA cases. To study renal repair we isolated and characterized human endothelial progenitor cells (hEPC) that were injected into mice treated with a sublethal dose of L-S. The human cells persisted in the kidney microvasculature of injured mice for 4 days but not in the uninjured control group. We also identified a novel function of PI3K catalytic subunit p110β in angiogenesis where in vitro analysis showed that p110β knockdown caused a defect in tip cell differentiation and sprouting formation, and decreased cellular migration and proliferation. in vivo analysis demonstrated that endothelial-restricted p110β ablation rendered the mice more susceptible to kidney injury and impaired renal microvasculature repair. In addition, we demonstrated an important role for platelet-derived growth factor B (PDGFB) in initiating kidney GEC repair mechanism as systemic inhibition of PDGFB by soluble PDGF receptor β led to high morbidity in the mice treated with a sublethal dose of L-S. In this thesis we developed an important animal model that can be used to further our understanding about the GEC injury and the potential application of EPC transplantation for renal restoration, and to gain more insights about the endogenous factors that govern the kidney microvascular repair mechanism.