2147-PUB: Change in Matrix Metalloproteinase Activity Is Associated with Zinc Level in the Development of Renal Changes in a Diabetic Preclinical Model

Abstract

Zinc is required for activation of Matrix Metalloproteinases (MMPs). Circulating zinc levels are decreased in diabetes1 and decreased activity of some MMPs is associated with the development of diabetic nephropathy (DN). The association between MMP activity and zinc in the development of DN has not been investigated and was examined in a preclinical model in this study. In this study, diabetic (DM: STZ: 3x 65mg/kg) male BALB/c mice were euthanized after 5, 10 and 30wks of diabetes. Age-matched mice acted as controls. At termination, kidneys, plasma and urine were collected for histopathology, measurement of biochemical parameters, total MMP activity using a broad spectrum MMP fluorogenic substrate and zinc level by ICPMS. In DM mice, blood glucose levels were increased at 5, 10 and 30wks (P<0.01) as were kidney/body weight (P<0.05) and urinary albumin/creatinine ratios (P<0.05). After 5wks of diabetes histopathological changes were evident and albumin/creatinine ratio increased (P<0.05). Urinary MMP activity was decreased (P<0.001) at 5wks and preceded a decrease in kidney and plasma MMP activity at 10 and 30wks (both P<0.05). DM decreased plasma but not urinary zinc levels at 10 and 30wks (both P<0.05). In DM mice, the kidney MMP activity correlated positively with plasma MMP activity (r=0.3774, P<0.03) and diabetes duration. Plasma zinc correlated with plasma MMP activity (r=-0.77, P=0.04) but only at 30wks. These results suggest an association between plasma MMP activity and zinc but only after a long duration of diabetes. The early decrease in urinary total MMP activity suggests it may have utility as a marker of early kidney disease. Whether this is so for human kidney disease is currently not known and requires further study. 1 Chabosseau and Rutter, Archives of Biochemistry and Biophysics (2016). Disclosure A. Tao: None. R. McQuilty: None. S.S. Sutanto: None. L.A. Ban: None. S.M. Twigg: Advisory Panel; Self; Abbott, AstraZeneca, Sanofi. Speaker’s Bureau; Self; Abbott, AstraZeneca, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. S. McLennan: None.