Ahrabi Ali K, Terryn Sara, Valenti Giovanna, Caron Nathalie, Serradeil-Le Gal Claudine, Raufaste Danielle, Nielsen Soren, Horie Shigeo, Verbavatz Jean-Marc, Devuyst Olivier
Division of Nephrology, UCL Medical School, Université Catholique de Louvain, 10 Avenue Hippocrate, B-1200 Brussels, Belgium.
J Am Soc Nephrol. 2007 Jun;18(6):1740-53. doi: 10.1681/ASN.2006010052. Epub 2007 May 2.
Mutations in PKD1 are associated with autosomal dominant polycystic kidney disease. Studies in mouse models suggest that the vasopressin (AVP) V2 receptor (V2R) pathway is involved in renal cyst progression, but potential changes before cystogenesis are unknown. This study used a noncystic mouse model to investigate the effect of Pkd1 haploinsufficiency on water handling and AVP signaling in the collecting duct (CD). In comparison with wild-type littermates, Pkd1(+/-) mice showed inappropriate antidiuresis with higher urine osmolality and lower plasma osmolality at baseline, despite similar renal function and water intake. The Pkd1(+/-) mice had a decreased aquaretic response to both a water load and a selective V2R antagonist, despite similar V2R distribution and affinity. They showed an inappropriate expression of AVP in brain, irrespective of the hypo-osmolality. The cAMP levels in kidney and urine were unchanged, as were the mRNA levels of aquaporin-2 (AQP2), V2R, and cAMP-dependent mediators in kidney. However, the (Ser256) phosphorylated AQP2 was upregulated in Pkd1(+/-) kidneys, with AQP2 recruitment to the apical plasma membrane of CD principal cells. The basal intracellular Ca(2+) concentration was significantly lower in isolated Pkd1(+/-) CD, with downregulated phosphorylated extracellular signal-regulated kinase 1/2 and decreased RhoA activity. Thus, in absence of cystic changes, reduced Pkd1 gene dosage is associated with a syndrome of inappropriate antidiuresis (positive water balance) reflecting decreased intracellular Ca(2+) concentration, decreased activity of RhoA, recruitment of AQP2 in the CD, and inappropriate expression of AVP in the brain. These data give new insights in the potential roles of polycystin-1 in the AVP and Ca(2+) signaling and the trafficking of AQP2 in the CD.
多囊肾病1（PKD1）基因突变与常染色体显性多囊肾病相关。小鼠模型研究表明，血管加压素（AVP）V2受体（V2R）途径参与肾囊肿进展，但囊肿形成前的潜在变化尚不清楚。本研究使用非囊肿小鼠模型，研究Pkd1单倍体不足对集合管（CD）水代谢及AVP信号传导的影响。与野生型同窝小鼠相比，尽管肾功能和水摄入量相似，但Pkd1(+/-)小鼠在基线时表现出不适当的抗利尿作用，尿渗透压较高，血浆渗透压较低。尽管V2R分布和亲和力相似，但Pkd1(+/-)小鼠对水负荷和选择性V2R拮抗剂的利水反应均降低。无论低渗状态如何，它们在脑中AVP表达均不适当。肾和尿中的cAMP水平未变，肾中aquaporin-2（AQP2）、V2R及cAMP依赖性介质的mRNA水平也未变。然而，在Pkd1(+/-)肾中，（Ser256）磷酸化的AQP2上调，且AQP2募集至CD主细胞的顶端质膜。分离的Pkd1(+/-) CD中基础细胞内Ca(2+)浓度显著降低，细胞外信号调节激酶1/2磷酸化下调，RhoA活性降低。因此，在无囊肿变化时，Pkd1基因剂量减少与不适当抗利尿综合征（正水平衡）相关，反映细胞内Ca(2+)浓度降低、RhoA活性降低、CD中AQP2募集及脑中AVP表达不适当。这些数据为多囊蛋白-1在AVP和Ca(2+)信号传导以及CD中AQP2转运中的潜在作用提供了新见解。
