Schulz Angela, Hänsch Jonna, Kuhn Kristina, Schlesener Maria, Kossmehl Peter, Nyengaard Jens R, Wendt Norbert, Huber Matthias, Kreutz Reinhold
Department of Clinical Pharmacology and Toxicology, CharitéCentrum für Therapieforschung, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Physiol Genomics. 2008 Sep 17;35(1):30-5. doi: 10.1152/physiolgenomics.90270.2008. Epub 2008 Jul 22.
The Munich Wistar Frömter (MWF) rat represents a genetic model with an inherited nephron deficit and exhibits mild hypertension and progressive albuminuria, which is more pronounced in males than females. Previously, we demonstrated in a consomic strain that replacement of a quantitative trait locus on chromosome 6 normalized the nephron deficit and suppressed albuminuria development, suggesting a link between the two findings. Here we tested the role of a second major locus linked to albuminuria in MWF on chromosome 8 and generated the consomic strain MWF-8(SHR) by transfer of chromosome 8 from spontaneously hypertensive rats (SHR) into MWF. The early onset of albuminuria at 8 wk of age in MWF (>50-fold increase compared with SHR) was significantly suppressed in consomic animals, and the development of marked proteinuria at 32 wk significantly diminished. Total nephron number in consomic rats (23,771 +/- 1,352) and MWF (27,028 +/- 1,322) were similar and significantly lower (-36%) compared with SHR (36,979 +/- 1,352, P < 0.0001). The development of mild albuminuria in female MWF was also significantly diminished in MWF-8(SHR). Thus, the development of overt and mild albuminuria in male and female MWF rats is not a mandatory consequence of the inherited nephron deficit. The locus on chromosome 8 appears of interest, because its exchange between MWF and SHR protects against the development of albuminuria in MWF-8(SHR) animals despite their inherited nephron deficit and higher systolic blood pressure.
慕尼黑威斯塔·弗勒姆特（MWF）大鼠是一种具有遗传性肾单位缺陷的遗传模型，表现出轻度高血压和进行性蛋白尿，在雄性大鼠中比雌性大鼠更为明显。此前，我们在一个代换系中证明，替换6号染色体上的一个数量性状位点可使肾单位缺陷正常化并抑制蛋白尿的发展，这表明这两个发现之间存在联系。在这里，我们测试了MWF大鼠8号染色体上与蛋白尿相关的第二个主要位点的作用，并通过将自发性高血压大鼠（SHR）的8号染色体转移到MWF中，培育出了代换系MWF-8（SHR）。代换系动物中，MWF在8周龄时出现的早期蛋白尿发作（与SHR相比增加了50倍以上）得到了显著抑制，32周时明显蛋白尿的发展也显著减少。代换系大鼠（23,771±1,352）和MWF大鼠（27,028±1,322）的总肾单位数量相似，与SHR（36,979±1,352，P<0.0001）相比显著更低（-36%）。雌性MWF大鼠中轻度蛋白尿的发展在MWF-8（SHR）中也显著减少。因此，雄性和雌性MWF大鼠中明显和轻度蛋白尿的发展并非遗传性肾单位缺陷的必然结果。8号染色体上的这个位点似乎很值得关注，因为尽管MWF-8（SHR）动物存在遗传性肾单位缺陷和较高的收缩压，但该位点在MWF和SHR之间的交换可防止其出现蛋白尿。
