Expression of matrix metalloproteinases MMP-2 and MMP-9 is altered during nephrogenesis in fetuses from diabetic rats.
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-beta1 (TGF-beta1) 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-beta1/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-beta1 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-beta 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-beta1/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.
Duong Van Huyen
Jean-Paul
JP
INSERM U652, IFR 58, Centre de recherche des Cordeliers, Université René Descartes (Paris 5), Paris, France. jean-paul.duong-van-huyen@hop.egp.ap-hop-paris.fr
Viltard
Mélanie
M
Nehiri
Touria
T
Freund
Nicole
N
Bélair
Marie-France
MF
Martinerie
Cécile
C
Lelongt
Brigitte
B
Bruneval
Patrick
P
Lelièvre-Pégorier
Martine
M
D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry / Q000201:enzymology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D038081:Organogenesis / Q000502:physiology*; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9