Matrix metalloproteinases (MMPs) are central to the homeostasis of the ECM and we have previously reported that their expression is altered in DN. In particular MMP-3, an MMP crucial for activation of other MMPs and for the degradation of proteoglycans was increased. Whether increased MMP-3 mRNA results in increased activity and its relationship with circulating MMP-3 is not known as was investigated in this study after short and long duration of diabetes.

 Diabetes was induced in 6 week old male C57BL/6 mice (STZ: 3x 65mg/kg), age-matched non-diabetic mice acted as control. Animals were euthanased after 10 and 30 weeks and kidney tissue was harvested for measurement of MMP-3 gene and MMP-3 protein by qRT-PCR and western blot analysis respectively, and total and specific MMP activity using a Sensolyte kit. Renal morphological changes were assessed by histology.

 After 30 weeks of diabetes early histological changes were evident with increased glomerular size, thickening of basement membrane in glomeruli of diabetic mice. Shown in the table, diabetes increased MMP-3 mRNA and protein at 30wks. Compared with CHOW fed animals, total kidney MMP activity was decreased with diabetes and by age albeit to a lesser extent. In contrast, decreased kidney MMP-3 activity was seen with diabetes but not age, with a greater decrease at 10 than 30 weeks. Plasma MMP-3 was also decreased at both time points studied (10 wks: CHOW 2.69±0.37 vs. Diabetic 2.03±0.13, 30wks: CHOW 0.71±0.10 vs. Diabetic 0.51±0.07, both P<0.05).

 This study shows a dichotomous relationship between MMP-3 mRNA and its protein and activity levels, suggesting post translational modification. These results suggest MMP-3 may be a mediator of the decreased MMP activities observed in this study. Whether circulating MMP-3 can be used as an early marker of DN remains to be investigated.