Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Germany.
J Hypertens. 2012 Oct;30(10):2031-8. doi: 10.1097/HJH.0b013e328356a60a.
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.
先天性肾单位缺失与动脉高血压的进展和慢性肾病的发生有关。与具有低级别蛋白尿的自发性高血压大鼠 (SHRs) 相比，慕尼黑威斯特法伦弗里姆特尔 (MWF) 近交系大鼠发展为高血压、进行性白蛋白尿，并表现出约 27%的遗传性肾单位缺失。将 SHRs 的大鼠染色体 (RNO)6 导入 MWF 大鼠中，可显著抑制 4 周龄 MWF-6 大鼠的白蛋白尿，并消除肾单位缺失。早期肾发生的差异可能导致 MWF 大鼠的肾单位缺失。
我们比较了 E15.5-E16.0 阶段匹配的 MWF 大鼠、SHRs 和同源 MWF-6 大鼠胚胎的输尿管芽分支形态发生和肾单位诱导。
对输尿管芽树的三维重建进行比较分析表明，定性分支形态发生正常。令人惊讶的是，MWF 大鼠的输尿管芽尖端数量高于 SHRs (+22%；P=0.004)。然而，MWF 大鼠的每个输尿管芽尖端诱导的肾单位数量明显低于 SHRs (-46%；P<0.0001)。MWF-6 大鼠部分纠正了这种缺陷 (+18%比 MWF；P=0.02)。在涉及肾脏发育的 59 个候选基因的基因表达分析中，与 SHRs 相比，胚胎肾脏中肝细胞生长因子 (Hgf) 基因的表达在 MWF 和 MWF-6 大鼠中显著降低（约 -70%；P<0.004）。
这些结果表明，在肾发生的早期阶段，MWF 大鼠的肾单位诱导效率降低，这部分取决于 RNO6 上的遗传位点。此外，位于 RNO4 上的 Hgf 可能是导致 MWF 大鼠肾单位缺失的一个有趣候选基因。
