Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in acute pyelonephritis and renal scarring

• Published in: Pediatric research Vol. 53; no. 4; pp. 698 - 705
• Main Authors: CHROMEK, Milan, TULLUS, Kjell, HERTTING, Olof, JAREMKO, Georg, KHALIL, Adli, LI, Ying-Hua, BRAUNER, Annelie
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.04.2003
• Subjects: Acute Disease; Animals; Bacterial diseases; Biological and medical sciences; Cell Line; Child; Child, Preschool; Cicatrix - metabolism; Cicatrix - pathology; Disease Models, Animal; Ent and stomatologic bacterial diseases; Epithelial Cells - cytology; Epithelial Cells - enzymology; Escherichia coli Infections - metabolism; Escherichia coli Infections - pathology; Female; Glomerular Mesangium - enzymology; Glomerular Mesangium - pathology; Human bacterial diseases; Humans; Infant; Infant, Newborn; Infectious diseases; Interstitial nephritis; Kidney Tubules - enzymology; Kidney Tubules - pathology; Leukocytes - enzymology; Matrix Metalloproteinase 9 - urine; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred Strains; Monocytes - enzymology; Monocytes - microbiology; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pyelonephritis - diagnostic imaging; Pyelonephritis - pathology; Pyelonephritis - urine; Radionuclide Imaging; Tissue Inhibitor of Metalloproteinase-1 - urine; Human; Kidney disease; Urinary system disease; Enzyme; Acute; Scar; Metalloendopeptidases; Gelatinase B; Ascending pyelonephritis; Infection; Peptidases; Tissue; Endopeptidase; Pyelonephritis; Hydrolases; Inhibitor; Child
• ISSN: 0031-3998; 1530-0447
• DOI: 10.1203/01.pdr.0000057575.86337.cb

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.