Expression of matrix metalloproteinases MMP-2 and MMP-9 is altered during nephrogenesis in fetuses from diabetic rats

Abstract

Remodeling of extracellular matrix (ECM) is an important physiological feature of normal growth and development. Recent studies have emphasized the role of matrix metalloproteinases (MMP-2 and MMP-9) in normal mouse nephrogenesis. We have demonstrated previously in the rat that in utero exposure to maternal diabetes impairs renal development leading to a 30% reduction in the nephron number. Transforming growth factor-b1 (TGF-b1) and connective tissue growth factor (CTGF) are known to mediate high glucose effects on matrix degradation. The aim of the present study was to address the expression of type IV collagenase and TGF-b1/CTGF systems in rat kidney during normal development and after in utero exposure to maternal diabetes. Both MMP-2 and MMP-9 mRNA metanephric expressions and activities were dramatically downregulated in kidneys issued from diabetic fetuses and in metanephros cultured in the presence of high glucose concentration. TGF-b1 and CTGF expressions were significantly enhanced in diabetic fetal kidneys and in high glucose cultured metanephroi. Conditioned media obtained from metanephroi grown with high glucose concentration upregulated functional TGF-b activity in transfected ATDC5 cells. In conclusion, in impaired nephrogenesis resulting from in utero exposure to maternal diabetes, alteration of both type IV collagenase and TGF-b1/ CTGF systems may lead to abnormal remodeling of ECM, which may, in turn, induce defects in ureteral bud branching leading to the observed reduction in the nephron number with consequences later in life: progression of chronic renal disease and hypertension. The development of the kidney is based on reciprocal induction between two mesodermally derivated tissues. Morphogenesis starts when the ureteric bud (UB) invades the metanephric mesenchyme and initiates reciprocal induction. The mesenchyme induces the UB to grow and branch to form the collecting ducts. The UB, in turn, induces the mesenchyme to undergo a mesenchymal to epithelial conversion to form nephrons via a series of morphogenetic events (aggregation of mesenchyme to form renal vesicles then S-shaped bodies and finally mature glomeruli). 1,2 Regulation of this process involves the participation of various DNAbinding proteins, that is, transcription factors, growth factors and their receptors, and proto-oncogenes acting as growth factor receptors. A constant remodeling of the extracellular matrix (ECM) is needed at the growing tips of the invading uretric bud to allow further branchings in the metanephric mesenchyme. 3,4 Production of ECM-degrading enzymes is expectedly linked to metanephric development to regulate the expression of ECM protein and ECM-related proteins by proteolytic processing. This creates a gradient of all these molecules in strategic locations with spatiotemporal distribution. 4 The ECM-degrading enzymes are collectively known as matrix metalloproteinases (MMPs) because their activity is dependent on the presence of metal ion, for example, Zn 2 þ . The activity of MMPs is inhibited by tissue...

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