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.

The 3H1 Br/+ mouse displays renal hypoplasia and this defect is associated with decreased embryological expression of Six2. The purpose of this study was to determine whether renal function is impaired in the adult Br heterozygous mutant. Expression of SIX2 occurred in wild‐type kidneys at E13.5, but it was significantly reduced in heterozygous siblings and absent in all newborn and adult kidneys. 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. Increased levels of ET‐1, ETA, ETB, and Na,K‐ATPase were present in the dilated renal tubules of mutant mice based on immunostaining. Features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were determined for mutant mice. These results indicate that adult Br/+ mice suffer from CRF associated with renal hypoplasia as well as glomerulopathy and a reduced number of glomeruli. Defects are associated with an absence of the SIX2 prenatally suggesting that this protein is critical for normal glomerular development and renal function in the adult. Supported by R01 info:ddbj-emblgenbank/DK064752 (SL).