BACKGROUND: Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. METHODS: Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. RESULTS: Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-D-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. CONCLUSIONS: Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.
BACKGROUND:Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. METHODS:Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. RESULTS: Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabeticmice. Serum levels of blood ureanitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-D-glucosaminidase were significantly elevated in diabeticMMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabeticMMP-2 KO mice. CONCLUSIONS: Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.
Authors: Carmen Mora-Fernández; Virginia Domínguez-Pimentel; Mercedes Muros de Fuentes; José L Górriz; Alberto Martínez-Castelao; Juan F Navarro-González Journal: J Physiol Date: 2014-06-06 Impact factor: 5.182
Authors: Andreia L Bates; Michael W Pickup; Miranda A Hallett; E Ashley Dozier; Stacy Thomas; Barbara Fingleton Journal: J Pathol Date: 2015-01-05 Impact factor: 7.996
Authors: Aline L Cortes; Sabrina R Gonsalez; Lilimar S Rioja; Simone S C Oliveira; André L S Santos; Minolfa C Prieto; Paulo A Melo; Lucienne S Lara Journal: Biochim Biophys Acta Mol Basis Dis Date: 2017-10-05 Impact factor: 5.187