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This Article Full Text Full Text (PDF) All Versions of this Article: 289/1/F49    most recent 00134.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Dou, W. Articles by Raghow, R. Search for Related Content PubMed PubMed Citation Articles by Dou, W. Articles by Raghow, R.

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

¹Department of Veterans Affairs Medical Center, Memphis; ²Advanced Research Group, Incyte Genomics, Palo Alto, California; Departments of ³Anatomy and Neurobiology and ⁴Medicine, The University of Tennessee Health Science Center, Memphis; ⁵Department of Medicine, Vanderbilt University Medical School, Nashville; and ⁶Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 14 April 2004 ; accepted in final form 18 February 2005

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.

prostaglandins; Escherichia coli

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