MWF rats with spontaneous albuminuria inherit a reduced efficiency of nephron induction during early nephrogenesis in comparison to SHR rats

Abstract

A congenital nephron deficit has been linked to the progression of arterial hypertension and to the development of chronic kidney disease. The Munich Wistar Frömter (MWF) inbred rat develops hypertension, progressive albuminuria, and exhibits an inherited nephron deficit of about 27% compared to spontaneously hypertensive rats (SHRs) with low-grade albuminuria. Introgression of rat chromosome (RNO)6 from SHRs into MWF rats markedly suppresses albuminuria and abolishes the nephron deficit in 4-week-old MWF-6 rats. Differences in early nephrogenesis may account for the nephron deficit in MWF rats. We compared ureteric bud branching morphogenesis and nephron induction in E15.5-E16.0 stage-matched rat embryos between MWF rats, SHRs, and consomic MWF-6 rats. Comparative analysis of three-dimensional reconstructions of the ureteric bud tree suggested normal qualitative branching morphogenesis. Surprisingly, the number of ureteric bud tips was higher in MWF rats compared to SHRs (+22%; P = 0.004). However, the nephron number induced per ureteric bud tip was markedly lower in MWF rats compared to SHRs (-46%; P < 0.0001). This deficit was partially corrected in MWF-6 rats (+18% vs. MWF; P = 0.02). In gene expression analysis of 59 candidate genes involved in kidney development, hepatocyte growth factor (Hgf) gene expression was significantly reduced in embryonic kidneys of MWF and MWF-6 rats (approximately -70%; P < 0.004) compared to SHRs. These results suggest a reduced efficiency of nephron induction in MWF rats during the early stages of nephrogenesis that is partially dependent on genetic loci on RNO6. In addition, Hgf that maps to RNO4 may represent an interesting candidate gene that contributes to the nephron deficit in MWF rats.