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Abstract
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.
Highlights
Statins are the first-line recommended pharmacological therapy in patients with dyslipidemias and for both primary [1] and secondary [2] prevention of coronary heart disease [3,4,5,6] (Table 1)
With a similar mechanism calcitonin, the hormone produced by parafollicular cells, increases aquaporin 2 (AQP2) apical targeting in vitro and in vivo by activating its Gs-coupled cognate receptor expressed in collecting duct renal cells and markedly ameliorates polyuria in vasopressindeficient Brattleboro rats [135]
Short-term exposure to simvastatin produces no change in cholesterol plasma membrane levels, but increases AQP2 accumulation in the apical membrane of principal cells of kidney slices from Brattleboro rats
Summary
Statins are the first-line recommended pharmacological therapy in patients with dyslipidemias and for both primary [1] and secondary [2] prevention of coronary heart disease [3,4,5,6] (Table 1). A recently identified ‘pleiotropic’ effect of statins is the increased expression levels of the renal membrane water channels Aquaporin 2 (AQP2). The long-term regulation (>24 hrs) of renal water permeability implies the overall effect on AQP2 gene and AQP2 protein abundance in the cell, under the AVP control [43, 54, 64].
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