An imbalance whereby glomerular extracellular matrix (ECM) production is increased and degradation is decreased leads to a relative and absolute increase in ECM volume in the diabetic mesangium. This crucical alteration impairs glomerular filtering capacity and results in glomerulosclerosis and end-stage renal disease. Plasminogen activator inhibitor-1 (PAI-1) is produced by mesangial cells in response to growth factor stimulation, is increased in glomeruli of diabetic animals and humans and, importantly, is a major factor preventing the degradation of mesangial ECM by inhibiting the activation of plasmin and metalloproteinases (MMP). We identified the presence of novel steroid receptors, which function as heterodimers, peroxisomal proliferator-activated receptors, PPARgamma, and retinoic acid receptor, RXRalpha, in cultured mesangial cells and in glomerular cores. PPARgamma activation substantially decreased PAI-1 expression, which likely resulted from inhibition of the nuclear effects of the mitogen activated protein kinase (MAPK) pathway. We hypothesize that PPARgamma activation will attenuate the development and progression of diabetic glomerulopathy.
Specific aims i nclude: 1) Demonstrate that administration of PPARgamma ligands or novel MAPK inhibitors will prevent glomerular structural changes in rats given streptozotocin (STZ).
This aim will determine whether PPARgamma activation affects the glomerulus in vivo, which would support our preliminary data. 2) Define the role of PAI-1 in mediating glomerulosclerosis.
This aim will examine changes in the PAI-1 system and MMP in cultured cells and in glomeruli of animal models treated with PPARgamma ligands. Importantly, PAI-1 knockout mice will be given STZ and the development of nephropathy will be compared with that of wild type controls. 3) Investigate the regulation and function of PPARgamma in cultured mesangial cells.
This aim will assess whether growth factors or the diabetic milieu alters PPARgamma or RXRalpha expression and examines the effects of receptor activation on mesangial cell growth, apoptosis, ECM and integrin expression. The major contribution of this proposal will be to develop a readily applicable, potential therapeutic approach to inhibit or attenuate the development of diabetic nephropathy by using PPARgamma ligands and to elucidate the mechanism by which activation of these receptors impact on critical cellular signaling pathways.
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