Pericytes in the kidney are the source of scar forming myofibroblasts and also pivotal cells in angiogenesis and vascular stabilization. Microvascular rarefaction following injury in the kidney is increasingly implicated in hypoxia, ischemia, chronic inflammation and progressive loss of renal function. We try to dissect whether injury-stimulated pericyte-endothelial crosstalk leads to not only migration and differentiation of pericytes into myofibroblasts but also destabilization of capillaries in the kidney. Therefore strategies to prevent microvascular rarefaction are highly desirable. VEGF is the key regulator of vasculogenesis and angiogenesis. Our previous study has proved that either blocking VEGF receptor signaling on endothelial cells or PDGF receptor signaling on pericytes prevents pericyte differentiation, proliferation, capillary rarefaction and attenuates renal fibrosis. VEGF receptor blockade also decreases recruitment of inflammatory cells. In UUO, an animal model of progressive renal fibrosis, we find VEGF isoforms switch from VEGF164 dominance to VEGF120 and VEGF188. Evidence in tumor angiogenesis has shown that VEGF120 and VEGF188 are associated with dysangiogenesis and poor tumor growth. We will study the pathogenic role of VEGF isoform switch in progressive renal fibrosis, focusing on capillary rarefaction and inflammation. In the first year, we will try to localize the expression of VEGF isoform in UUO, IRI and 5/6Nx kidneys. In the second year, we will use VEGF188 conditional knockout mice to study the role of VEGF isoform switch, from VEGF164 to VEGF120/188 dominance, in progressive renal fibrosis. We will use three different VEGF deletion mice. The VEGF188 will be deleted since embryonic stage in all cells in the first strain. In the second one, we will use conditional VEGF knockout induced by tamoxifen administration in all cells. We will also try to delete VEGF188 only in renal tubule cells in another mouse strain. In the third year, we will use inducible overexpression system to overexpress VEGF188 in renal tubule cells to study the pathogenic role of VEGF188 in kidney. We hope to develop novel therapies to prevent microvascular rarefaction and kidney fibrosis with the most minimal adverse effects through targeting specific VEGF isoform in progressive kidney disease.
|Effective start/end date||8/1/15 → 7/31/16|