Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice

Background Genetic ablation of cyclooxygenase-2 (COX-2) resulted in cystic renal dysplasia and early death in adult mice. The ontologic development of the renal pathology and the biochemical and physiological abnormalities as sociated with the dysplasia are unknown. Methods. Mice homozygous for a targeted deletion of COX-2 (-/-) were compar ed with wild-type littermates (+/+). Somatic and kidney growth and renal hi stology were studied at the day of birth and at a number of postnatal ages. Systolic blood pressure, urinalysis, urine osmolality, serum and urine che mistries, and inulin clearance were evaluated in adult animals. Results. Beginning at postnatal day 10 (PN10), kidney growth was suppressed in -/- animals, while somatic growth and heart growth were unaffected. By PN10, -/- kidneys had thin nephrogenic cortexes and crowded, small, subcaps ular glomeruli. The pathology increased with age with progressive outer cor tical dysplasia, cystic subcapsular glomeruli, loss of proximal tubular mas s, and tubular atrophy and cyst formation. Adult -/- kidneys had profound d iffuse tubular cyst formation, outer cortical glomerular hypoplasia and per iglomerular fibrosis, inner cortical nephron hypertrophy, and diffuse inter stitial fibrosis. The glomerular filtration rate was reduced by more than 5 0% in -/- animals (6.82 +/- 0.65 ML/min/kg) compared with wild-type control s (14.7 +/- 1.01 mL/min/kg, P < 0.001). Plasma blood urea nitrogen and crea tinine were elevated in null animals compared with controls. Blood pressure , urinalysis, urine osmolality, and other plasma chemistries were unaffecte d by the deletion of COX-2. Conclusions. Deficiency of COX-2 results in progressive and specific renal architectural disruption and functional deterioration beginning in the fina l phases of nephrogenesis. Tissue-specific and time-dependent expression of COX-2 appears necessary for normal postnatal renal development and the mai ntenance of normal renal architecture and function.