Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases |
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| Authors: | S V McLennan D J Kelly A J Cox Z Cao J G Lyons D K Yue R E Gilbert |
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| Institution: | (1) University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia, AU;(2) Kanematsu Institute, RPA Hospital, Sydney, New South Wales, Australia, AU;(3) Department of Medicine, University of Sydney, Sydney, New South Wales, Australia, AU;(4) Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre (Repat Campus), Victoria, Australia, AU |
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| Abstract: | Aims/hypothesis: Extracellular matrix accumulation is thought to be involved in the pathogenesis of diabetic nephropathy. Increased matrix
synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting,
have not been fully explored. Furthermore, the effect of renoprotective therapies on matrix accumulation through these pathways
has not been examined. We investigated the degradative pathway of type IV collagen and the effects of ACE inhibition in experimental
diabetic nephropathy.
Methods: Diabetes was induced in 16 rats by administrating streptozocin; 8 of the diabetic rats were allocated at random to receive
the ACE inhibitor perindopril (2 mg/l) in their drinking water and 8 age and weight matched rats served as controls. Gene
expression of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) was measured by RT-PCR and type IV collagen content by immunohistochemistry. MMP activities were determined by degradation
of a radiolabelled substrate and by zymography.
Results: Six months of diabetes was associated with a decrease in mRNA and enzymatic activity of MMP-9 (21 % and 51 % respectively,
p < 0.05 vs control) and a 51 % increase in TIMP-1 mRNA (p < 0.05 vs control). By contrast, MMP-2 mRNA was increased but its activity decreased (43 % and 43 % respectively, p < 0.05 vs control). Total degradative capacity of kidney tissue from diabetic rats was also lower (Control: 48 ± 7 %, Diabetic:
33 ± 6 %, p < 0.05). Activation of latent MMPs with amino-phenylmercuric acetate increased matrix degradation by two-fold. However the
relative decrease associated with experimental diabetes still remained. All diabetes-associated changes in MMP and TIMP mRNA
and activities were attenuated by perindopril treatment in association with reduced type IV collagen accumulation.
Conclusions/interpretation: These results indicate that the impairment of matrix degradation contributes to matrix accumulation in diabetic nephropathy
and that the beneficial effects of ACE inhibition could in part be mediated by modulation of changes in matrix degradative
pathways. Diabetologia (2002) 45: 268–275]
Received: 13 June 2001 and in revised form: 14 September 2001 |
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| Keywords: | Matrix metalloproteinase diabetic nephropathy angiotensin converting enzyme extracellular matrix type IV collagen |
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