Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice

Kidney Int. 2014 Jul;86(1):127-38. doi: 10.1038/ki.2014.10. Epub 2014 Feb 12.


X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 2 / metabolism
  • Cyclic AMP / metabolism
  • Diabetes Insipidus, Nephrogenic / complications*
  • Diabetes Insipidus, Nephrogenic / drug therapy*
  • Diabetes Insipidus, Nephrogenic / physiopathology
  • Disease Models, Animal
  • Exocytosis
  • Fatty Acids, Monounsaturated / administration & dosage*
  • Fluvastatin
  • Gene Expression
  • Humans
  • Indoles / administration & dosage*
  • Kidney Tubules, Collecting / drug effects
  • Kidney Tubules, Collecting / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Polyuria / drug therapy*
  • Polyuria / etiology*
  • Polyuria / physiopathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Gastrointestinal Hormone / metabolism
  • Receptors, Vasopressin / deficiency
  • Receptors, Vasopressin / genetics
  • Secretin / administration & dosage*


  • Aqp2 protein, mouse
  • Aquaporin 2
  • Fatty Acids, Monounsaturated
  • Indoles
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone
  • Receptors, Vasopressin
  • secretin receptor
  • Secretin
  • Fluvastatin
  • Cyclic AMP