Deficient embryonic expression of SIX2 is associated with decreased glomerular number and chronic renal failure in the adult 3H1 Br/+ mouse.

Abstract

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).