V F Norwood1, S G Morham, O Smithies. 1. Department of Pediatrics, University of Virginia, Charlottesville, Virginia 22908, USA. vfn6t@virginia.edu
Abstract
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.
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 ureanitrogen 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.
Authors: Ursula Vitt; Darryl Gietzen; Kristian Stevens; Jim Wingrove; Shanya Becha; Sean Bulloch; John Burrill; Narinder Chawla; Jennifer Chien; Matthew Crawford; Craig Ison; Liam Kearney; Mary Kwong; Joe Park; Jennifer Policky; Mark Weiler; Renee White; Yuming Xu; Sue Daniels; Howard Jacob; Michael I Jensen-Seaman; Jozef Lazar; Laura Stuve; Jeanette Schmidt Journal: Genome Res Date: 2004-04 Impact factor: 9.043
Authors: Manshan Xu; Shilpa Choudhary; Olga Voznesensky; Qi Gao; Douglas Adams; Vilmaris Diaz-Doran; Qian Wu; David Goltzman; Lawrence G Raisz; Carol C Pilbeam Journal: Bone Date: 2010-05-13 Impact factor: 4.398
Authors: Liming Wang; Yonggang Sha; Jingyi Bai; William Eisner; Matthew A Sparks; Anne F Buckley; Robert F Spurney Journal: Am J Physiol Renal Physiol Date: 2017-05-10
Authors: Charlotte Wagner; Helga Vitzthum; Hayo Castrop; Karl Schumacher; Michael Bucher; Sybille Albertin; Thomas M Coffman; William J Arendshorst; Armin Kurtz Journal: Pflugers Arch Date: 2003-09-19 Impact factor: 3.657