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Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases.
Diabetologia. 2002 Feb; 45(2):268-75.D

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.

Authors+Show Affiliations

Department of Medicine, University of Sydney, New South Wales, Australia. sue@med.usyd.edu.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11935159

Citation

McLennan, S V., et al. "Decreased Matrix Degradation in Diabetic Nephropathy: Effects of ACE Inhibition On the Expression and Activities of Matrix Metalloproteinases." Diabetologia, vol. 45, no. 2, 2002, pp. 268-75.
McLennan SV, Kelly DJ, Cox AJ, et al. Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases. Diabetologia. 2002;45(2):268-75.
McLennan, S. V., Kelly, D. J., Cox, A. J., Cao, Z., Lyons, J. G., Yue, D. K., & Gilbert, R. E. (2002). Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases. Diabetologia, 45(2), 268-75.
McLennan SV, et al. Decreased Matrix Degradation in Diabetic Nephropathy: Effects of ACE Inhibition On the Expression and Activities of Matrix Metalloproteinases. Diabetologia. 2002;45(2):268-75. PubMed PMID: 11935159.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases. AU - McLennan,S V, AU - Kelly,D J, AU - Cox,A J, AU - Cao,Z, AU - Lyons,J G, AU - Yue,D K, AU - Gilbert,R E, PY - 2002/4/6/pubmed PY - 2002/8/1/medline PY - 2002/4/6/entrez SP - 268 EP - 75 JF - Diabetologia JO - Diabetologia VL - 45 IS - 2 N2 - 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. SN - 0012-186X UR - https://www.unboundmedicine.com/medline/citation/11935159/Decreased_matrix_degradation_in_diabetic_nephropathy:_effects_of_ACE_inhibition_on_the_expression_and_activities_of_matrix_metalloproteinases_ L2 - https://doi.org/10.1007/s00125-001-0730-4 DB - PRIME DP - Unbound Medicine ER -