Role of metalloproteases and inhibitors in the occurrence and progression of diabetic renal lesions

Renal remodelling in hyperinsulinic/insulinopenic states is mediated by glu cotoxicity, endothelial dysfunction and vascular and nephron collagen turno ver. Hypertensive and renal links are renewed by renoprotective interventio ns of renin-angiotensin. Vasoactive peptide processing and vascular collage n deposition are under the tight control of two zinc metalloproteinase fami lies that regulate vascular tone and trophicity: gluzincins (or vasopeptida ses) are convertases of angiotensins, endothelins or atrial natriuretic fac tors; and metzincins [or matrix metalloproteases (MMS matrixins)] regulate vascular type IV collagen basement membrane proteolysis. Association of nat ural tissue inhibitors of MMPs, pharmacological inhibitors of vasopeptidase s [either conventional (angiotensin-converting enzyme inhibitors) or innova tive (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 bas ic to clinical stages. A leucocyte-endothelial transmigration model was des igned for transcription and addressing of enzymes and inhibitors, in situ m atrix degradation, and blockading by metalloprotease inhibitors (captopril) . Insulin-resistant fructose-fed rats showed heavy proteinuria and glomerul osclerosis involving angiotensin II-dependent changes in renal gelatinases and inhibitors. Urinary gelatinolytic profiles from Type 2 diabetic patient s with overt nephropathy were compared with those of normal first-degree re latives and age-matched healthy controls. Physiologically, MMP-9 was the pr imary urinary gelatinolytic enzyme. In Type 2 diabetic proteinuric patients , MMP-9 and MMP-2 releases were significantly increased in the absence of r enin-angiotensin blockade, while first-deg ree relatives showed reduced gel atinase levels suggestive of a genetic control of renal matrix regulation p rior to potential glycaemic dysregulation. These preliminary data suggest t hat local MMP/TIMP imbalance is involved in diabetic renal remodelling. Fur ther studies are needed to define the redundancies and specificities of vas opeptidase and MMP inhibitors, differentiate the antihypertensive effect fr om target-organ protection, screen for innovative pharmacological compounds , and validate simple, efficient biological markers of renal fibrosis progr ession and the effect of anti-fibrotic therapeutic interventions.