A novel therapeutic effect of statins on nephrogenic diabetes insipidus

Statins competitively inhibit hepatic 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, resulting in reduced plasma total and low‐density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional ‘pleiotropic’ effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate‐derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up‐regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high‐powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed.