The early stages of diabetes are characterized with increases in arterial pressure being transmitted to the kidney leading to elevations in glomerular capillary pressure (Pgc) which eventually cause development of proteinuria and renal injury. However, the mechanism by which increases in Pgc promote diabetic nephropathy (DN) is unclear. The Dahl salt-sensitive (SS) rat is a low-renin, salt-sensitive dependent model of hypertension that is highly susceptible to development of hypertension-induced renal disease when challenged with a high salt (HS) diet. In preliminary experiments, we observed that induction of diabetes with streptozotocin (STZ) in SS rats produced severe proteinuria with renal histological abnormalities characteristic of patients with DN. Matrix metalloproteinases (MMPs) have emerged as potential downstream candidate genes that contribute to the development of focal glomerulosclerosis and renal interstitial fibrosis.
In other preliminary studies, we observed that the activity of MMP-2 and -9 in the renal cortex were increased during the development of diabetes-induced renal injury in SS rats treated with STZ. These findings led to our current hypothesis that hyperglycemia induced by STZ in SS rats promotes the development of diabetic nephropathy by altering renal hemodynamics leading to an increase in the transmission of pressure to the glomerulus (Pgc) and initiating a cascade of events that increases MMP activity and promotes the development of proteinuria, renal fibrosis and progressive renal disease.
The novel aspects of these studies are that they will evaluate the use of the MMP inhibitor, XL784, on the development of renal injury in our diabetic model of renal injury(STZ-SS rat) and will take advantage of the Zinc-finger (Zn) knockout strategy to test the role of MMP-2 (Zn MMP-2 KO SS strain)in the development of renal disease in STZ-SS rats. These studies will provide compelling evidence that MMPs play a critical role in the progression of renal injury associated with diabetes and that MMP inhibitors of may emerge as a treatment for DN.