Meprin metalloproteases confer resistance to urinary tract infections

Abstract

Meprins are membrane-bound and secreted zinc metalloproteases that are expressed by kidney proximal tubules, intestinal epithelial cells, and leukocytes. They are found in the urinary tract, the intestinal lumen, and at sites of inflammation. The secreted form of meprin, composed of alpha subunits, is a large multimer capable of degrading bacterial proteins and shedding proteins from the cell surface. It was hypothesized that high levels of urinary meprin confer resistance to urinary tract infections (UTIs). Urine samples from healthy and UTI infected women were collected for analysis. Quantitative Western blotting showed that 89% of healthy women had low or undetectable levels of urinary meprin. In contrast, the majority (86%) of women suffering from an acute UTI had high levels of meprin protein in the urine. To examine susceptibility of different meprin genotypes to UTI, both wild-type and meprin alpha knockout mice were infected with Escherichia coli (E. coli) via transurethral catheterization. Bacterial counts in bladder show that meprin alpha knockout mice have 50 times greater number of E. coli versus wild-type. In addition, kidney bacterial counts in meprin alpha knockout mice were 13 fold greater in comparison to wild-type. These data indicate that meprin expression confers resistance to infections of the urinary tract. (NIH Grant DK 19691)