Submitted on September 15, 2008
Revised on January 20, 2009
Accepted on February 2, 2009
Deficiency in Six2 during prenatal development is associated with reduced nephron number, chronic renal failure, and hypertension in Br/+ adult mice
Ben Fogelgren1, Shiming Yang2, Ian C. Sharp2, Odaro J. Huckstep2, Wenbin Ma3, Jack Somponpun4, Edward C. Carlson5, Catherine Uyehara4, and Scott Lozanoff2*
1 University of Hawaii
2 University of Hawai'i School of Medicine
3 U.S. Food and Drug Administration
4 Tripler Army Medical Center
5 University of North Dakota School of Medicine and Health Sciences
* To whom correspondence should be addressed. E-mail: lozanoff{at}hawaii.edu.
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, while individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared to normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A (ETA) and B (ETB), 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.
