Role of metalloproteases and inhibitors in the occurrence and progression of diabetic renal lesions.
Renal remodelling in hyperinsulinic/insulinopenic states is mediated by glucotoxicity, endothelial dysfunction and vascular and nephron collagen turnover. Hypertensive and renal links are renewed by renoprotective interventions of renin-angiotensin. Vasoactive peptide processing and vascular collagen deposition are under the tight control of two zinc metalloproteinase families that regulate vascular tone and trophicity: gluzincins (or vasopeptidases) are convertases of angiotensins, endothelins or atrial natriuretic factors; and metzincins or matrix metalloproteases (MMP, matrixins)] regulate vascular type IV collagen basement membrane proteolysis. Association of natural tissue inhibitors of MMPs, pharmacological inhibitors of vasopeptidases [either conventional (angiotensin-converting enzyme inhibitors) or innovative (omapatrilat)], together with synthetic MMP inhibitors, are currently screened to counteract vascular remodelling and renal scarring. Our studies focused on the 72 kDa (MMP-2) and 92 kDa (MMP-9) matrixin gelatinases and tissue inhibitors involved in basement membrane degradation and rebuilding. Three complementary settings were developed, allowing evaluations from basic to clinical stages. A leucocyte-endothelial transmigration model was designed for transcription and addressing of enzymes and inhibitors, in situ matrix degradation, and blockading by metalloprotease inhibitors (captopril). Insulin-resistant fructose-fed rats showed heavy proteinuria and glomerulosclerosis involving angiotensin II-dependent changes in renal gelatinases and inhibitors. Urinary gelatinolytic profiles from Type 2 diabetic patients with overt nephropathy were compared with those of normal first-degree relatives and age-matched healthy controls. Physiologically, MMP-9 was the primary urinary gelatinolytic enzyme. In Type 2 diabetic proteinuric patients, MMP-9 and MMP-2 releases were significantly increased in the absence of renin-angiotensin blockade, while first-degree relatives showed reduced gelatinase levels suggestive of a genetic control of renal matrix regulation prior to potential glycaemic dysregulation. These preliminary data suggest that local MMP/TIMP imbalance is involved in diabetic renal remodelling. Further studies are needed to define the redundancies and specificities of vasopeptidase and MMP inhibitors, differentiate the antihypertensive effect from target-organ protection, screen for innovative pharmacological compounds, and validate simple, efficient biological markers of renal fibrosis progression and the effect of anti-fibrotic therapeutic interventions.
Service de Nephrologie, CHU Grenoble BP 217, 38043 Grenoble Cedex, France.
P
P
Zaoui
J F
JF
Cantin
M
M
Alimardani-Bessette
F
F
Monier
S
S
Halimi
F
F
Morel
D
D
Cordonnier
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D018450:Disease Progression; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases