Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus.
Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus.
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DOI：
10.1371/journal.pone.0101753
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Blount MA
中科院分区：
文献类型：
--
作者：
Sim JH;Himmel NJ;Redd SK;Pulous FE;Rogers RT;Black LN;Hong SM;von Bergen TN;Blount MA
锂，一种有效的抗精神病药物，在约40%的患者中诱发肾源性尿崩症（NDI）。浓缩尿的能力下降可能是由于锂急性破坏cAMP途径并慢性降低髓质内尿素转运蛋白（UT-A1）和水通道（AQP2）的表达。靶向另一种信号通路，如pkc介导的信号通路，可能是治疗锂诱导多尿的有效方法。pkc - α缺失小鼠（PKCα KO）和菌株匹配野生型（WT）对照分别用锂治疗0、3和5天。治疗3天和5天后，WT小鼠的尿量增加，尿渗透压降低，而PKCα KO小鼠的尿量和浓度没有变化。Western blot分析显示，WT小鼠3、5 d后髓质组织AQP2表达降低；然而，AQP2在PKCα KO中没有变化。UT-A1表达的结果类似。动物也用锂治疗6周。锂处理的WT小鼠的尿量增加了19倍，而PKCα KO处理的动物的尿量增加了4倍。在锂处理6周的WT动物中，AQP2和UT-A1表达降低，而在PKCα KO小鼠中，AQP2仅降低2倍，UT-A1表达不受影响。尿钠、钾和钙在锂喂养的WT小鼠中升高，而在PKCα KO小鼠中没有升高。我们的数据显示，在锂诱导的NDI中，消融PKCα可保持AQP2和UT-A1蛋白的表达和定位，并防止锂治疗相关的严重多尿的发生。
Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCα KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCα KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCα KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCα KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCα KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCα KO mice. Our data show that ablation of PKCα preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.
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影响因子：
6.1
作者：
Boone, Michelle;Kortenoeven, Marleen;Deen, Peter M. T.
通讯作者：
Deen, Peter M. T.
影响因子：
82.9
作者：
Braz, JC;Gregory, K;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
13.6
作者：
Lim, Sun Woo;Ahn, Kyung Ohk;Kwon, H. Moo
通讯作者：
Kwon, H. Moo
DOI：
10.1017/s1461145707008395
发表时间：
2008-06-01
影响因子：
4.8
作者：
Mann, Liad;Heldman, Eliahu;Agam, Galila
通讯作者：
Agam, Galila
DOI：
10.1073/pnas.0604073103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Kamsteeg, Erik-Jan;Hendriks, Giel;Deen, Peter M. T.
通讯作者：
Deen, Peter M. T.