1. Academic Validation
  2. Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus

Aliskiren increases aquaporin-2 expression and attenuates lithium-induced nephrogenic diabetes insipidus

  • Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F914-F925. doi: 10.1152/ajprenal.00553.2016.
Yu Lin 1 Tiezheng Zhang 1 Pinning Feng 2 Miaojuan Qiu 1 Qiaojuan Liu 1 Suchun Li 1 Peili Zheng 1 Yonglun Kong 1 Moshe Levi 3 Chunling Li 1 Weidong Wang 4
Affiliations

Affiliations

  • 1 Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; and.
  • 3 Department of Medicine, Division of Hypertension and Renal Diseases, University of Colorado Denver, Aurora, Colorado.
  • 4 Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; wangwd6@mail.sysu.edu.cn.
Abstract

The direct Renin Inhibitor aliskiren has been shown to be retained and persist in medullary collecting ducts even after treatment is discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal Aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were fed with either normal chow or LiCl diet (40 mmol·kg dry food-1·day-1 for 4 days and 20 mmol·kg dry food-1·day-1 for the last 3 days) for 7 days. Some mice were intraperitoneally injected with aliskiren (50 mg·kg body wt-1·day-1 in saline). Aliskiren significantly increased protein abundance of aquaporin-2 (AQP2) in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and phosphorylated AQP2 at serine 256 (pS256-AQP2) protein abundance, which was significantly inhibited both by adenylyl cyclase inhibitor MDL-12330A and by PKA Inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in the inner medulla of the kidney. In conclusion, the direct Renin Inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus likely via cAMP-PKA pathways.

Keywords

aquaporin; cAMP; direct renin inhibitor; urinary concentration.

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