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Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice
V F Norwood1, S G Morham, O Smithies
1Department of Pediatrics, University of Virginia, Charlottesville, Virginia 22908, USA. vfn6t@virginia.edu
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 associated with the dysplasia are unknown.
Methods:
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.
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, 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.
Conclusions:
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.
Insights
Genetic ablation of cyclooxygenase-2 (COX-2) causes progressive kidney disease in mice. This COX-2 deficiency leads to severe renal dysplasia, impaired kidney function, and abnormal kidney development.
Area of Science:
- Nephrology
- Developmental Biology
- Genetics
Background:
- Genetic deletion of cyclooxygenase-2 (COX-2) in mice leads to cystic renal dysplasia and early mortality.
- The developmental trajectory and functional consequences of this renal pathology remain largely unknown.
Purpose of the Study:
- To investigate the ontogeny of renal pathology in mice lacking COX-2.
- To characterize the biochemical and physiological abnormalities associated with COX-2 deficiency-induced renal dysplasia.
Main Methods:
- Comparison of homozygous COX-2 knockout mice (-/-) with wild-type littermates (+/+).
- Assessment of somatic and kidney growth, renal histology, blood pressure, urinalysis, and renal function (inulin clearance) at various postnatal ages and in adulthood.
Main Results:
- COX-2 deficient mice exhibited suppressed kidney growth starting at postnatal day 10.
- Histological analysis revealed progressive renal dysplasia, including cystic glomeruli, tubular atrophy, and fibrosis, in -/- mice.
- Adult -/- mice showed significantly reduced glomerular filtration rate (>50% decrease) and elevated blood urea nitrogen and creatinine levels.
Conclusions:
- COX-2 deficiency results in specific, progressive renal architectural disruption and functional decline starting during nephrogenesis.
- Tissue-specific and time-dependent expression of COX-2 is crucial for normal postnatal kidney development and function.