Leptin Increases Expression and Activity of Matrix Metalloproteinase-2 and Does Not Alter Collagen Production in Rat Glomerular Mesangial Cells

Abstract

Obesity is a leading risk factor for the development of nephropathy. In nephropathy, one of the major structural alterations found in the kidney is the increase in, or altered profile of, extracellular matrix (ECM) proteins such as collagen. Excessive synthesis and decreased degradation of matrix proteins by proteases such as matrix metalloproteinases (MMPs) may contribute to this process. We hypothesized that alterations observed in nephropathy may be due to alterations in direct effects of leptin, the product of the obesity gene. Here, we investigate the effect of leptin on collagen synthesis and MMP-2 production in rat glomerular mesangial cells. Using quantitative real-time PCR we showed that leptin does not alter the expression of collagen type I and IV mRNA. In keeping with this observation, proline incorporation was not altered by leptin. We also demonstrate that leptin induces MMP-2 expression in glomerular mesangial cells, assessed by quantitative real-time PCR. Analysis of conditioned media by gelatin zymography indicated increased activity at a molecular weight corresponding with that of MMP-2 in leptin-treated samples. In summary, our results indicate that leptin induces MMP-2 expression and activity without altering collagen synthesis, suggesting that normal leptin function has the potential to prevent ECM accumulation.

Keywords:

• Extracellular
• Matrix
• Metalloproteinase
• Collagen
• Obesity
• Leptin

ACKNOWLEDGMENTS

Funding was provided by the Canadian Diabetes Association via a scholarship award to Dr. Gary Sweeney in honor of the late Mary A. Bodington and by the Natural Sciences and Engineering Research Council of Canada (NSERC). The authors also acknowledge support of the Ontario Ministry of Economic Development and Trade via a Premier’s Research Excellence Award. Funding from the Canada Foundation for Innovation and Ontario Innovation Trust is also acknowledged.