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 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.
Dou
Wenkai
W
Department of Veterans Affairs Medical Center, Memphis, TN 38104, USA.
Thompson-Jaeger
Sandra
S
Laulederkind
Stanley J F
SJ
Becker
John W
JW
Montgomery
Julia
J
Ruiz-Bustos
Eduardo
E
Hasty
David L
DL
Ballou
Leslie R
LR
Eastman
P Scott
PS
Srichai
Betsy
B
Breyer
Matthew D
MD
Raghow
Rajendra
R
D000818:Animals; D051546:Cyclooxygenase 2; D004927:Escherichia coli Infections / Q000235:genetics / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009088:Mucoproteins / Q000096:biosynthesis*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000502:physiology; D014552:Urinary Tract Infections / Q000235:genetics / Q000503:physiopathology*; D058949:Uromodulin
D009088:Mucoproteins; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases