Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in acute pyelonephritis and renal scarring.
The aim of the present study was to elucidate the role of matrix metalloproteinase-9 (MMP-9), and its main inhibitor tissue inhibitor of metalloproteinases-1 (TIMP-1), in acute pyelonephritis and the process of renal scarring. Urine samples from 40 children with acute pyelonephritis, 16 children at 6-wk follow-up and 15 children with nonrenal fever were analyzed using ELISA. MMP-9 and TIMP-1 levels were compared with the outcome of pyelonephritis as measured by renal static scintigraphy. A mouse model of acute ascending pyelonephritis was used to localize the sites of production and the kinetics of MMP-9 and TIMP-1 using immunohistochemistry and ELISA. Human renal epithelial A498 cells, primary mesangial cells and monocytic THP-1 cells were stimulated by Escherichia coli. MMP-9 and TIMP-1 mRNA was analyzed by reverse transcription-PCR (RT-PCR) and protein production by ELISA. We demonstrate a significant increase of MMP-9 and TIMP-1 in the urine of children with acute pyelonephritis. Both proteins were produced mainly by leukocytes, and TIMP-1 also by resident kidney cells. Cells reacted differently after stimulation by bacteria. In mesangial cells and monocytes a decreased constitutive TIMP-1 production was found, which was in contrast to epithelial cells. Out of 40 children with pyelonephritis, 23 had higher urinary TIMP-1 than MMP-9 levels. These children had significantly more severe changes in both acute and follow-up scintigraphy scans indicating higher degree of acute tissue damage and renal scarring. Thus, our findings suggest an association between TIMP-1 and the process of renal scarring.
Chromek
Milan
M
Department of Clinical Microbiology, Microbiology and Tumorbiology Center, Karolinska Hospital, Stockholm, Sweden.
Tullus
Kjell
K
Hertting
Olof
O
Jaremko
Georg
G
Khalil
Adli
A
Li
Ying-Hua
YH
Brauner
Annelie
A
D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D004927:Escherichia coli Infections / Q000378:metabolism / Q000473:pathology; D005260:Female; D005920:Glomerular Mesangium / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007684:Kidney Tubules / Q000201:enzymology* / Q000473:pathology; D007962:Leukocytes / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000652:urine*; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000201:enzymology / Q000382:microbiology; D011704:Pyelonephritis / Q000000981:diagnostic imaging / Q000473:pathology / Q000652:urine*; D011877:Radionuclide Imaging; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000652:urine*
D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9