title: COX-2 gene dosage-dependent defects in kidney development.
abstract: Deletion of cyclooxygenase (COX)-2 causes impairment of kidney development, including hypothrophic glomeruli and cortical thinning. A critical role for COX-2 is seen 4-8 days postnatally. The present study was aimed at answering whether different COX-2 gene dosage and partial pharmacological COX-2 inhibition impairs kidney development. We studied kidney development in COX-2(+/+), COX-2(+/-), and COX-2(-/-) mice as well as in C57Bl6 mice treated postnatally with low (5 mg·kg(-1)·day(-1)) and high (10 mg·kg(-1)·day(-1)) doses of the selective COX-2 inhibitor SC-236. COX-2(+/-) mice exhibit impaired kidney development leading to reduced glomerular size but, in contrast to COX-2(-/-) mice, only marginal cortical thinning. Moreover, in COX-2(+/-) and COX-2(-/-) kidneys, juxtamedullary glomeruli, which develop in the very early stages of nephrogenesis, also showed a size reduction. In COX-2(+/-) kidneys at the age of 8 days, we observed significantly less expression of COX-2 mRNA and protein and less PGE2 and PGI2 synthetic activity compared with COX-2(+/+) kidneys. The renal defects in COX-2(-/-) and COX-2(+/-) kidneys could be mimicked by high and low doses of SC-236, respectively. In aged COX-2(+/-) kidneys, glomerulosclerosis was observed; however, in contrast to COX-2(-/-) kidneys, periglomerular fibrosis was absent. COX-2(+/-) mice showed signs of kidney insufficiency, demonstrated by enhanced serum creatinine levels, quite similar to COX-2(-/-) mice, but, in contrast, serum urea remained at the control level. In summary, function of both COX-2 gene alleles is absolutely necessary to ensure physiological development of the mouse kidney. Loss of one copy of the COX-2 gene or partial COX-2 inhibition is associated with distinct renal damage and reduced kidney function.
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany; and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Slattery
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany; and.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Frölich
authors.affiliation: Fraunhofer IME, Goethe-University, Frankfurt, Germany.
authors.forename: Yannik
authors.initials: Y
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany; and r.m.nuesing@med.uni-frankfurt.de.
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Nüsing
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D007668:Kidney / Q000254:growth & development*; D008297:Male; D008810:Mice, Inbred C57BL; D011720:Pyrazoles; D013449:Sulfonamides; D000096926:Benzenesulfonamides
chemical_list: D051546:Cyclooxygenase 2; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C077623:Ptgs2 protein, mouse
keywords: cyclooxygenase-2; kidney development; nephrogenesis; prostaglandins