Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

被引:89
作者
Lu, Xiaohan [1 ,2 ,3 ]
Wang, Fei [1 ,2 ,3 ]
Xu, Chuanming [3 ]
Soodvilai, Sunny [1 ,2 ]
Peng, Kexin [1 ,2 ,3 ]
Su, Jiahui [3 ]
Zhao, Long [1 ,2 ]
Yang, Kevin T. [1 ,2 ]
Feng, Yumei [4 ,5 ]
Zhou, Shu-Feng [6 ]
Gustafsson, Jan-Ake [7 ]
Yang, Tianxin [1 ,2 ,3 ]
机构
[1] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA
[2] Vet Affairs Med Ctr, Salt Lake City, UT 84108 USA
[3] Sun Yat Sen Univ, Zhongshan Sch Med, Inst Hypertens, Guangzhou 510080, Guangdong, Peoples R China
[4] Univ Nevada, Sch Med, Dept Pharmacol, Reno, NV 89557 USA
[5] Univ Nevada, Sch Med, Dept Physiol & Cell Biol, Reno, NV 89557 USA
[6] Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL 33620 USA
[7] Univ Houston, Dept Biol & Biochem, Houston, TX 77004 USA
基金
中国国家自然科学基金;
关键词
soluble (pro)renin receptor; liver X receptor; aquaporin-2; frizzled-8; beta-catenin; PRO RENIN RECEPTOR; VACUOLAR H+-ATPASE; DIABETES-INSIPIDUS; PRORENIN RECEPTOR; NUCLEAR RECEPTORS; ACTIVATION; EXPRESSION; KIDNEY; HYPERTENSION; CHOLESTEROL;
D O I
10.1073/pnas.1602397113
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The extracellular domain of the (pro) renin receptor (PRR) is cleaved to produce a soluble (pro) renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent beta-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.
引用
收藏
页码:E1898 / E1906
页数:9
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