Deletion of cyclooxygenase-2 (COX-2) causes impairment of kidney development including hypothrophic glomeruli and cortical thinning. A critical role for COX-2 is seen 4 to 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/d) and high doses (10 mg/kg/d) of selective COX-2 inhibitor SC-236. COX-2+/- mice exhibit impaired kidney development leading to reduced glomerular size but in contrast to COX-2-/- only marginal cortical thinning. Moreover in COX-2+/- and COX-2-/- kidneys juxtamedullary glomeruli which develop in the very early stages of nephrogenesis also show 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 to COX-2+/+. The renal defects in COX-2-/- and COX-2+/- 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-/- periglomerular fibrosis was absent. COX-2+/- mice show signs of kidney insufficiency, demonstrated by enhanced serum creatinine levels, quite similar to COX-2-/-, but in contrast serum urea remained at 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.
- kidney development
- Copyright © 2015, American Journal of Physiology - Renal Physiology