Norwood V F, Morham S G, Smithies O
Department of Pediatrics, University of Virginia, Charlottesville, Virginia 22908, USA.
Kidney Int. 2000 Dec;58(6):2291-300. doi: 10.1046/j.1523-1755.2000.00413.x.
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 associated with the dysplasia are unknown.
Mice homozygous for a targeted deletion of COX-2 (-/-) were compared with wild-type littermates (+/+). Somatic and kidney growth and renal histology were studied at the day of birth and at a number of postnatal ages. Systolic blood pressure, urinalysis, urine osmolality, serum and urine chemistries, and inulin clearance were evaluated in adult animals.
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, subcapsular glomeruli. The pathology increased with age with progressive outer cortical dysplasia, cystic subcapsular glomeruli, loss of proximal tubular mass, and tubular atrophy and cyst formation. Adult -/- kidneys had profound diffuse tubular cyst formation, outer cortical glomerular hypoplasia and periglomerular fibrosis, inner cortical nephron hypertrophy, and diffuse interstitial fibrosis. The glomerular filtration rate was reduced by more than 50% in -/- animals (6.82 +/- 0.65 mL/min/kg) compared with wild-type controls (14.7 +/- 1.01 mL/min/kg, P < 0. 001). Plasma blood urea nitrogen and creatinine were elevated in null animals compared with controls. Blood pressure, urinalysis, urine osmolality, and other plasma chemistries were unaffected by the deletion of COX-2.
Deficiency of COX-2 results in progressive and specific renal architectural disruption and functional deterioration beginning in the final phases of nephrogenesis. Tissue-specific and time-dependent expression of COX-2 appears necessary for normal postnatal renal development and the maintenance of normal renal architecture and function.
环氧化酶-2（COX-2）的基因消融导致成年小鼠出现多囊性肾发育异常并早期死亡。肾病理的本体发育以及与发育异常相关的生化和生理异常尚不清楚。
将靶向缺失COX-2的纯合子小鼠（-/-）与野生型同窝小鼠（+/+）进行比较。在出生当天和多个出生后年龄段研究了躯体和肾脏生长以及肾脏组织学。对成年动物评估了收缩压、尿液分析、尿渗透压、血清和尿液化学指标以及菊粉清除率。
从出生后第10天（PN10）开始，-/-动物的肾脏生长受到抑制，而躯体生长和心脏生长未受影响。到PN10时，-/-小鼠的肾脏肾皮质变薄，肾小球拥挤、小且位于被膜下。随着年龄增长，病理变化加剧，出现进行性外侧皮质发育异常、被膜下肾小球囊肿、近端肾小管数量减少、肾小管萎缩和囊肿形成。成年-/-小鼠的肾脏有广泛的弥漫性肾小管囊肿形成、外侧皮质肾小球发育不全和肾小球周围纤维化、内侧皮质肾单位肥大以及弥漫性间质纤维化。与野生型对照相比，-/-动物的肾小球滤过率降低了50%以上（6.82±0.65 mL/min/kg），而野生型对照为（14.7±1.01 mL/min/kg，P<0.001）。与对照相比，基因敲除动物的血浆尿素氮和肌酐升高。血压、尿液分析、尿渗透压和其他血浆化学指标不受COX-2缺失的影响。
COX-2缺乏导致在肾发生的最后阶段开始出现进行性和特异性的肾脏结构破坏和功能恶化。COX-2的组织特异性和时间依赖性表达似乎是出生后正常肾脏发育以及维持正常肾脏结构和功能所必需的。
