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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/F1166    most recent 90550.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fogelgren, B. Articles by Lozanoff, S. Search for Related Content PubMed PubMed Citation Articles by Fogelgren, B. Articles by Lozanoff, S.

Deficiency in Six2 during prenatal development is associated with reduced nephron number, chronic renal failure, and hypertension in Br/+ adult mice

¹Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu; ³Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, Hawaii; ²Laboratory of Retrovirus Research, Division of Viral Products, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland; and ⁴Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota

Submitted 15 September 2008 ; accepted in final form 2 February 2009

The Br/+ mutant mouse displays decreased embryological expression of the homeobox transcription factor Six2, resulting in hertitable renal hypoplasia. The purpose of this study was to characterize the renal physiological consequences of embryonic haploinsuffiency of Six2 by analyzing renal morphology and function in the adult Br heterozygous mutant. Adult Br/+ kidneys weighed 50% less than those from wild-type mice and displayed glomerulopathy. Stereological analysis of renal glomeruli showed that Br/+ kidneys had an average of 88% fewer glomeruli than +/+ kidneys, whereas individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared with normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A (ET_A) and B (ET_B), and Na-K-ATPase were present in the dilated renal tubules of mutant mice. Physiological features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were measured in Br/+ mutant mice. Electron microscopy of the Br/+ glomeruli revealed pathological alterations such as hypercellularity, extracellular matrix accumulation, and a thick irregular glomerular basement membrane. These results indicate that adult Br/+ mice suffer from CRF associated with reduced nephron number and renal hypoplasia, as well as glomerulopathy. Defects are associated with embryological deficiencies of Six2, suggesting that proper levels of this protein during nephrogenesis are critical for normal glomerular development and adult renal function.

Br mutant mouse; glomerulus