CYCLOOXYGENASE-2 IN RAT NEPHRON DEVELOPMENT

The inducible second isoform of cyclooxygenase (COX-2) that mediates i nflammation also is expressed at low levels in normal adult rat kidney s and is upregulated in response to noninflammatory stimuli (R. C. Har ris, J. A. McKanna, Y. Akai, H. R. Jacobson, R. N. DuBois, and M. D. B reyer. J. Clin. Invest. 94: 2504-2510, 1994). Roles in morphogenesis a re indicated by reported teratogenicity of COX inhibitors and renal dy sgenesis in COX-2 knockout mice (J. E. Dinchuk, B. D. Car, R. J. Focht , J. J. Johnston, B. D. Jaffee, M. B. Covington, N. R. Contel, V. Prl. Eng, R. J. Collins, P. M. Czerniak, A. G. Stewart, and J. M. Trzaskos , Nature 378: 406-409, 1995; S. G. Morham, R. Lagenbach, C. D. Loftin, H. F. Tiano, N. Vouloumanos, J. C. Jennette, J. F. Mahler, K. D. Kluc kman, A. Ledford, C. A. Lee, and O. Smithies. Cell 83: 473-482, 1995). Blots from developing rat kidneys demonstrated that COX-2 mRNA and im munoreactive protein were present in neonates, peaked in the 2nd and 3 rd postnatal weeks and declined to adult levels by the 3rd month. Immu nolocalization and in situ hybridization detected intense COX-2 immuno reactivity and mRNA in a subset of thick ascending limb epithelial cel ls near the macula densa in each developing nephron; after 2 wk the CO X-2 gradually waned. These data demonstrate that COX-2 expression is s ubject to normal developmental regulation and can be sustained over ex tended periods; they also support the conclusion that metabolites of C OX-2 play important roles in the differentiation and early functions o f mammalian nephrons.