Profiling renal sodium transporters in mice with nephron Ift88 disruption: Association with sex, cysts, and blood pressure.
Profiling renal sodium transporters in mice with nephron Ift88 disruption: Association with sex, cysts, and blood pressure.
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DOI：
10.14814/phy2.15206
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发表时间：
2022-03
影响因子：
2.5
通讯作者：
Kohan DE
中科院分区：
文献类型：
--
作者：
Hu C;Lakshmipathi J;Stuart D;Kohan DE
由于Ift 88基因破坏导致的肾单位初级纤毛缺失导致性别和年龄特异性表型，涉及肾囊肿形成、血压（BP）和尿Na+排泄。先前的研究表明，在2个月大时接受肾单位特异性Ift 88基因破坏诱导的雄性小鼠在囊性前病变时出现血压降低和盐诱导的尿钠增多。（诱导后2个月），并在诱导后9个月时变为高血压伴明显囊性肾;相比之下，雌性Ift 88 KO小鼠在诱导后2个月未表现出独特的表型，并且在诱导后9个月BP轻度降低。本研究利用这些Ift 88 KO小鼠研究肾脏Na+转运蛋白和通道蛋白表达的相关变化。在诱导后2个月，囊性前雄性Ift 88 KO小鼠的高盐饮食相关总NKCC 2水平降低，而雌性小鼠的Na+转运蛋白或通道无变化。在诱导后9个月，囊性雄性Ift 88 KO小鼠在正常和高盐饮食中的总NHE 3和磷酸化NHE 3水平增加，同时NKCC 2、磷酸化和/或总NCC和ENaC-α表达降低。相比之下，诱导后9个月的雌性Ift 88 KO小鼠在高盐摄入期间除了磷酸化NCC增加外，Na+转运蛋白或通道没有变化。因此，囊性前的BP降低和肾囊性雄性Ift 88 KO小鼠的BP升高与肾单位Na+转运蛋白/通道表达的独特性别依赖性变化相关。我们发现，NKCC 2在缺乏肾单位纤毛的雄性小鼠中下调;这与先前报道的相对较低的血压有关。此外，我们发现，NHE 3是不受管制的雄性小鼠缺乏纤毛谁开发多囊肾，这是与高血压，如前所述。
Loss of nephron primary cilia due to disruption of the Ift88 gene results in sex‐ and age‐specific phenotypes involving renal cystogenesis, blood pressure (BP) and urinary Na+ excretion. Previous studies demonstrated that male mice undergoing induction of nephron‐specific Ift88 gene disruption at 2 months of age developed reduced BP and increased salt‐induced natriuresis when pre‐cystic (2 months post‐induction) and became hypertensive associated with frankly cystic kidneys by 9 months post‐induction; in contrast, female Ift88 KO mice manifested no unique phenotype 2 months post‐induction and had mildly reduced BP 9 months post‐induction. The current study utilized these Ift88 KO mice to investigate associated changes in renal Na+ transporter and channel protein expression. At 2 months post‐induction, pre‐cystic male Ift88 KO mice had reduced high salt diet associated total NKCC2 levels while female mice had no alterations in Na+ transporters or channels. At 9 months post‐induction, cystic male Ift88 KO mice had increased total and phosphorylated NHE3 levels together with reduced NKCC2, phosphorylated and/or total NCC, and ENaC‐α expression on normal and high salt diets. In contrast, female Ift88 KO mice at 9 months post‐induction had no changes in Na+ transporters or channels beyond an increase in phosphorylated‐NCC during high salt intake. Thus, reduced BP in pre‐cystic, and elevated BP in renal cystic, male Ift88 KO mice are associated with unique sex‐dependent changes in nephron Na+ transporter/channel expression. We found that NKCC2 is downregulated in male mice lacking nephron cilia; this is associated with relatively low blood pressure as previously reported. In addition, we found that NHE3 is unregulated in male mice lacking cilia who have developed polycystic kidneys; this is associated with hypertension as previously reported.
影响因子：
3.5
作者：
Hovater MB;Olteanu D;Hanson EL;Cheng NL;Siroky B;Fintha A;Komlosi P;Liu W;Satlin LM;Bell PD;Yoder BK;Schwiebert EM
通讯作者：
Schwiebert EM