(provided by candidate) The hallmark pathologic feature of diabetic glomerulosclerosis is mesangial expansion. In diabetic nephropathy (DN), mesangial expansion is the critical lesion that leads to the known clinical features. Increased levels of glucose, insulin, and angiotensin II (ANG ll) both cooperatively and independently stimulate the production of transforming growth factor-beta 1, which then promotes extracellular matrix (ECM) protein expansion, particularly fibronectin, laminin and collagen, by upregulating their synthesis and down-regulating their degradation. Interaction between MCs and ECM proteins occur via integrin receptors (with alpha and beta sub-units), which can be blocked by synthetic Arg-Gly-Asp (RGD) peptides and integrin antibodies. Unlike antiserum, which may cause severe side effects, cyclic RGD peptides are currently available as an effective anti-thrombotic and anti-cancer agent in humans as well as in treating ischemia-induced acute renal failure in rats. However, no-one has looked at the potential benefit of RGD peptides in treating DN. Integrin signaling is important in cellular physiology and pathophysiology. RGD peptides have also been used to define the mechanisms of integrin-mediated signaling in other cell types, but not in MC. The hypothesis of this application is that integrin-mediated attachment induces positive feedback of integrin and ECM gene expression in DN. Our preliminary studies show that RGD peptides significantly inhibited MC adhesion to fibronectin, laminin and collagen and significantly increased alpha 1, alpha 5, and beta 1 integrin sub-units in glomeruli of streptozotocin (STZ)-induced diabetic rats. Also, ANG II and insulin increased integrin expression and the IC50 of RGD peptide to inhibit MC fibronectin adhesion.
The Specific Aims are 1) to quantitate the effects of cyclic RGD peptides on the progression of DMGS in STZ-induced diabetic rats; 2) to determine whether FAK, the MAPK and Pl3 kinase signaling pathways are activated by integrin-mediated MC-ECM adhesion, using RGD peptides. The successful completion of this study can provide a novel and feasible target for treatment in DN.
| Basgen, John M; Nicholas, Susanne B; Mauer, Michael et al. (2006) Comparison of methods for counting cells in the mouse glomerulus. Nephron Exp Nephrol 103:e139-48 |
