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1 Department of Veterans Affairs Medical Center, Memphis, TN, USA
2 Advanced Research Group, Incyte Genomics, Palo Alto, CA, USA
3 Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, USA
4 Department of Veterans Affairs Medical Center, Memphis, TN, USA; Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, USA
5 Department of Veterans Affairs Medical Center, Memphis, TN, USA; Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
6 Department of Medicine, Vanderbilt University Medical School, Nashville, TN, USA
7 Department of Veterans Affairs Medical Center, Memphis, TN, USA; Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: rraghow{at}utmem.edu.
Mice lacking a functional COX-2 gene develop abnormal kidneys that contain hypoplastic glomeruli and reduced proximal tubular mass, and 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. Down regulation of EGF could potentially affect renal development, and THP/uromodulin gene has been implicated in abnormal kidney development and end-stage renal failure in man. 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 immuno-histological 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 uro-pathogenic Escherichia coli.
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