Physiological insights into novel therapies for nephrogenic diabetes insipidus.

Abstract

Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high.

• Authors: Jeff M Sands, Janet D Klein
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 311 Issue 6 Pg. F1149-F1152 (12 01 2016) ISSN: 1522-1466 [Electronic] United States
• PMID: 27534996 (Publication Type: Journal Article, Review, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Aquaporin 2
• Receptors, Vasopressin
• Metformin
• Simvastatin
• Sildenafil Citrate
• Erlotinib Hydrochloride
• Adenylate Kinase

Topics

• Adenylate Kinase (metabolism)
• Animals
• Aquaporin 2 (metabolism)
• Diabetes Insipidus, Nephrogenic (drug therapy, genetics, metabolism)
• Erlotinib Hydrochloride (pharmacology, therapeutic use)
• Humans
• Metformin (pharmacology, therapeutic use)
• Mutation
• Phosphorylation (drug effects)
• Receptors, Vasopressin (genetics, metabolism)
• Sildenafil Citrate (pharmacology, therapeutic use)
• Simvastatin (pharmacology, therapeutic use)