Preeclampsia and angiogenesis inhibitors used to treat cancer are two common causes of severe glomerular endothelial injury. The glomerular endothelium depends on vascular endothelial growth factor (VEGF) made by podocytes to maintain endothelial stability and integrity. A deficiency of VEGF signaling at the glomerular endothelium causes endotheliosis, a dysfunction of endothelial cells manifested clinically by proteinuria and hypertension. This disorder is seen in both preeclampsia (due to a soluble receptor that blocks VEGF signaling) and as a complication of cancer treatment with several angiogenesis inhibitors directed against VEGF. The clinical consequences in preeclampsia include increased maternal and fetal complications, while with angiogenesis-based cancer treatment the consequence is dose-limiting toxicity for highly effective anti-cancer drugs. Extracellular nucleotides such as ATP, as well as their hydrolysis product adenosine, are important factors in determining the health of the endothelium. In general, extracellular ATP is pro-inflammatory and pro-thrombotic, while adenosine protects against inflammation and thrombosis. Cell surface enzymes called ectonucleotidases convert extracellular ATP to adenosine, promoting a stable milieu for the vascular endothelium. We hypothesize that adenosine signaling via cell surface adenosine receptors is an important component of protection from injury in settings of VEGF deficiency.
In aim 1 of this proposal, we will determine if a non-selective adenosine agonist can reverse albuminuria and renal injury in mice with VEGF deficiency.
In aim 2, we will identify the specific adenosine receptor (A1, A2a, A2b, or A3) that mediates the protective effect of adenosine on the glomerular endothelium by using selective adenosine agonists and antagonists to ameliorate or accentuate renal injury in our mouse model. These studies will help define pathways that mediate renal injury in states of VEGF deficiency, and will also identify specific targets for drug therapy. A wide range of adenosine agonists and antagonists have already been developed, with several in clinical trials, so that clinical applications could be considered without a long delay between bench and bedside.
In diseases such as pre-eclampsia or complications of some cancer therapies, the kidney is injured by lack of important growth factors. We are developing strategies that might allow prevention or reversal of this kidney injury. Our findings may reduce severe complications of pregnancy or allow for more effective delivery of cancer chemotherapy.
