Defective expression of Tamm-Horsfall protein/uromodulin in COX-2-deficient mice increases their susceptibility to urinary tract infections

Mice lacking a functional cyclooxygenase-2 (COX-2) gene develop abnormal kidneys that contain hypoplastic glomeruli and reduced proximal tubular mass, and they often die of renal failure. A comparison of kidney-specific gene expression between wild-type and COX-2-deficient mice by cDNA microarrays r...

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Published in:American journal of physiology. Renal physiology 2005-07, Vol.58 (1), p.F49-F60
Main Authors: WENKAI DOU, THOMPSON-JAEGER, Sandra, BREYER, Matthew D, RAGHOW, Rajendra, LAULEDERKIND, Stanley J. F, BECKER, John W, MONTGOMERY, Julia, RUIZ-BUSTOS, Eduardo, HASTY, David L, BALLOU, Leslie R, EASTMAN, P. Scott, SRICHAI, Betsy
Format: Article
Language:English
Subjects:
Bacteria
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Gene expression
Kidneys
Proteins
Vertebrates: urinary system
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Summary:Mice lacking a functional cyclooxygenase-2 (COX-2) gene develop abnormal kidneys that contain hypoplastic glomeruli and reduced proximal tubular mass, and they often die of renal failure. A comparison of kidney-specific gene expression between wild-type and COX-2-deficient mice by cDNA microarrays revealed that although more than 500 mRNAs were differentially expressed between the two strains of mice depending on their ages, the genes encoding pre-pro-epidermal growth factor (pre-pro-EGF) and Tamm-Horsfall protein (THP)/uromodulin were aberrantly expressed in the kidneys of COX-2 mice at all stages of their development. Downregulation of EGF could potentially affect renal development, and THP/uromodulin gene has been implicated in abnormal kidney development and end-stage renal failure in humans. We assessed in detail mechanism of defective THP/uromodulin gene expression and its potential consequences in COX-2-deficient mice. Consistent with the microarray data, the steady-state levels of THP/uromodulin mRNA were severely reduced in the COX-2 kidney. Furthermore, reduced expression of renal THP/uromodulin, as assessed by Western blot and immunohistological methods, was closely corroborated by a corresponding decline in the urinary secretion of THP/uromodulin in COX-2 mice. Finally, we demonstrate that the bladders of COX-2 mice, in contrast to those of the wild-type mice, are highly susceptible to colonization by uropathogenic Escherichia coli. [PUBLICATION ABSTRACT]
ISSN:1931-857X
1522-1466