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Matrix metalloproteinase-2 in a murine model of infantile-type polycystic kidney disease
1Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City 66160-7400, USA.
Abstract:
It was previously found that elevated levels of matrix metalloproteinase (MMP)-2 (gelatinase A) and -9 (gelatinase B) were synthesized and secreted into the medium by cultured kidney tubules derived from cystic C57BL/6J-cpk mice. To determine whether increased synthesis and secretion occur in vivo in this mouse model of polycystic kidney disease, kidney protein extracts, mRNA, and tissue sections were compared for expression and activity of MMP-2 and -9. Although both MMP were detected in tissue extracts, the differences in expression levels and activity in normal and cystic kidneys were far greater for MMP-2. High levels of MMP-2 seemed to result from increased expression by the cystic kidneys predominantly in the second and third postnatal weeks (a time when the kidneys are undergoing rapid cystic enlargement). Much of the increased MMP was present in the inactive zymogen form, although active enzyme was readily detected by sodium dodecyl sulfate-polyacrylamide gel zymography and in situ zymography. MMP-2 was abnormally localized to the interstitium and to foci between cysts, suggesting that MMP-2 may regulate collagen accumulation at those sites, thus allowing cyst enlargement and limiting the severity of interstitial fibrosis.
Insights
Matrix metalloproteinase (MMP)-2 levels increase in cystic kidneys of polycystic kidney disease mice. This suggests MMP-2 plays a role in cyst enlargement and interstitial fibrosis in this disease model.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Elevated matrix metalloproteinase (MMP)-2 and -9 were previously found in cultured kidney tubules from cystic mice.
- Polycystic kidney disease (PKD) involves progressive kidney cyst development and enlargement.
Purpose of the Study:
- To investigate in vivo the expression and activity of MMP-2 and MMP-9 in a mouse model of PKD.
- To determine the role of MMPs in the pathogenesis of kidney cyst formation and enlargement.
Main Methods:
- Comparison of kidney protein extracts, mRNA, and tissue sections from normal and cystic C57BL/6J-cpk mice.
- Analysis of MMP-2 and MMP-9 expression levels and enzymatic activity using zymography techniques.
Main Results:
- MMP-2 showed significantly greater differences in expression and activity between normal and cystic kidneys compared to MMP-9.
- Increased MMP-2 expression in cystic kidneys was prominent during the second and third postnatal weeks, coinciding with rapid cyst enlargement.
- MMP-2 was detected in both inactive zymogen and active forms, with abnormal localization to the interstitium and between cysts.
Conclusions:
- Elevated MMP-2 expression and activity in vivo contribute to cyst enlargement in this PKD mouse model.
- Abnormal MMP-2 localization suggests a role in regulating collagen accumulation, facilitating cyst growth and influencing interstitial fibrosis severity.