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COX-2 gene dosage-dependent defects in kidney development

: Slattery, P.; Frölich, S.; Schreiber, Y.; Nüsing, R.M.


American journal of physiology. Renal physiology 310 (2016), Nr.10, S.F1113-F1122
ISSN: 1931-857X
ISSN: 0363-6127
ISSN: 1522-1466
ISSN: 0002-9513
Deutsche Forschungsgemeinschaft DFG
Fraunhofer IME ()

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 and high (10 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 PGE(2) and PGI(2) 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.