Diabetic nephropathy (DN) is the leading course of end-stage renal disease. Although multiple cell types are involved, DN is in essence a microvascular disease that develops as a result of a confluence of hemodynamic and metabolic perturbations. Endothelial cells and its disorders play a major role in this disease. In the past decade, a large body of studies has shown that excessive angiogenic signals and unregulated glomerular endothelial growth is a key pathogenic mechanism of DN. VEGF/VEGFR was shown to serve as a driving force of this. However, the role of anti-angiogenic pathway in this disease is largely unknown, yet the magnitude and spectrum of angiogenic signals are determined by the balance between angiogenic and anti- angiogenic signals. Given the fact that endothelial receptor protein tyrosine kinases (RPTKs) play a major role in transduction of angiogenic signals, we have advanced the hypothesis that endothelial receptor protein tyrosine phosphatases (RPTPs), counter-enzymes of RPTKs, may induce anti-angiogenic signals. We have isolated a receptor-type PTP CD148 from glomerular endothelial cells and shown that CD148 has a potent activity in suppressing endothelial growth factor signals (including VEGFR) and in inhibiting endothelial cell growth and angiogenesis. Further, we have recently found that thrombospondin-1(TSP1), an anti-angiogenic protein, acts as a ligand for CD148. These findings suggest that CD148 functions as a key regulator of glomerular angiogenic response. In this application we therefore define the role of CD148 in DN. Based on our preliminary data and anti-angiogenic activity of CD148, the following hypotheses were advanced; 1) CD148 expression/activity is decreased in diabetic glomerular endothelium. This enhances angiogenic endothelial growth factor signals (including VEGFR) and promotes the development and progression of DN. 2) Activation of CD148 suppresses angiogenic growth factor signals in diabetic glomerular endothelium and restores the functional and structural changes of DN.
In aim 1, we will determine the role of CD148 in DN by manipulating CD148 expression in diabetic mice using conditional knockout and transgenic mice.
In aim2, we will determine the effects of CD148 activation in DN by treating diabetic mice with the CD148 agonists, a specific TSP1 fragment and an agonistic antibody.
Aim 3 will determine the endothelial signaling and function which is regulated by CD148 in diabetic glomerular endothelial cells, by knocking-down or activating CD148 in high-glucose glomerular endothelial culture and in diabetic glomeruli in vivo (in mice). Thus, the proposed studies will define the role of CD148 anti- angiogenic pathway in DN and explore a new strategy for the treatment of this disease.
Anti-angiogenesis treatment to inhibit excessive angiogenic signals and unregulated blood vessel growth in diabetic kidney is thought to be a promising therapeutic strategy for diabetic kidney disease. The proposed experimental study will define the roles and the effects of CD148 tyrosine phosphatase, a newly identified anti- angiogenic endothelial receptor, in diabetic kidney disease and explore a new treatment strategy for this disease.
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