The Kidney Institute, Dept. of Medicine, Univ. of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-3018, USA.
Am J Physiol Renal Physiol. 2010 Nov;299(5):F1078-86. doi: 10.1152/ajprenal.00504.2009. Epub 2010 Aug 18.
Polycystic kidney disease (PKD) in Han:SPRD Cy rats is caused by a missense mutation in Anks6 (also called Pkdr1), leading to an R823W substitution in SamCystin, a protein that contains ankyrin repeats and a sterile alpha motif (SAM). The cellular function of SamCystin and the role of the Cy (R823W) mutation in cyst formation are unknown. In normal SPRD rats, SamCystin was found to be expressed in proximal tubules and glomeruli; protein expression was highest at 7 days of age and declined by ∼50-60% at 45-84 days of age. In Cy/+ and Cy/Cy kidneys, expression of SamCystin was lower than in +/+ kidneys at 3 and 7 days but became elevated at 21 days. Immunohistochemical analysis revealed that SamCystin was distributed on the brush border of proximal tubules in normal rat kidneys. In Cy/+ kidneys, there were robust SamCystin staining in cyst-lining epithelial cells and loss of apical localization, and increased number of PCNA-positive cells in cyst-lining epithelia. Verapamil, an L-type Ca(2+) channel blocker, accelerated PKD progression in this model and caused a further increase in the expression and abnormal distribution of SamCystin. We conclude that aberrant expression and mislocalization of R823W SamCystin lead to increased cell proliferation and renal cyst formation.
多囊肾病（PKD）在 Han:SPRD Cy 大鼠中是由 Anks6（也称为 Pkdr1）中的错义突变引起的，导致 SamCystin 中的 R823W 取代，SamCystin 是一种含有锚蛋白重复序列和无菌α基序（SAM）的蛋白质。SamCystin 的细胞功能以及 Cy（R823W）突变在囊肿形成中的作用尚不清楚。在正常的 SPRD 大鼠中，发现 SamCystin 在近端小管和肾小球中表达；蛋白表达在 7 天时最高，在 45-84 天时下降约 50-60%。在 Cy/+和 Cy/Cy 肾脏中，SamCystin 的表达在 3 天和 7 天时低于 +/+肾脏，但在 21 天时升高。免疫组织化学分析显示，SamCystin 在正常大鼠肾脏的近端小管刷状缘上分布。在 Cy/+肾脏中，囊壁上皮细胞中存在强烈的 SamCystin 染色，顶端定位丧失，并且囊壁上皮细胞中的 PCNA 阳性细胞数量增加。维拉帕米是一种 L 型钙（Ca2+）通道阻滞剂，在该模型中加速 PKD 进展，并导致 SamCystin 的表达和异常分布进一步增加。我们得出结论，R823W SamCystin 的异常表达和定位错误导致细胞增殖增加和肾脏囊肿形成。
