Urinary AQP2 Excretion in Hypercholesterolemic Patients as a Measure of Effect of Statin Therapy

Statins are the first-line recommended pharmacological therapy in patients with dyslipidemias and play a key role in both primary and secondary prevention of coronary heart disease. By decreasing plasma total and low-density lipoprotein cholesterol (LDL-C) concentrations, statins decrease the risks for atherosclerotic cardiovascular disease and associated morbidity and mortality. Statins occupy part of the active binding site of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) and inhibit its enzymatic activity in the liver, a key step leading to the reduction of cellular sterol pool. Statins also have beneficial effects on the vascular wall by stabilizing the atherosclerotic plaques, ameliorating impaired endothelial function, and reducing vascular inflammation.

Besides the well-known metabolic and cardiovascular effects, it has been recently shown that statins increase the plasma membrane expression of the renal water channels Aquaporin 2 (AQP2). Water reabsorption in the kidney connecting tubule and collecting duct is regulated by the antidiuretic hormone arginine vasopressin (AVP), which promotes plasma membrane expression of the water channe aquaporin 2 (AQP2), the rate-limiting step controlling reabsorption of water, thus urine concentration, in this segment of the nephron. The investigators reported a number of evidences showing that statins accumulate AQP2 at the apical membrane of collecting duct cells by a AVP-independent mechanism. The effect of statins on AQP2 is independent of classical cholesterol homeostasis but rather depends on depletion of mevalonate-derived intermediates of cholesterol synthetic pathways, i.e. isoprenoid intermediates, including farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP).

Water balance disorders are often associated with defects of AQP2 trafficking. Nephrogenic Diabetes Insipidus (NDI) is characterized by the inability of the kidney to respond to AVP stimulation and is caused by either mutations in AQP2 or vasopressin type-2 receptor (AVPR2) genes. Mutations in the AVPR2 gene lead to X-linked NDI (X-NDI). This cause of 90% of all diagnosed congenital NDI cases.

Conventional treatment of X-NDI patients consists in low-sodium, low-protein diet and the administration on thiazide diuretics sometimes in combination with indomethacin or amiloride. Although these drugs cause some relief of X-NDI symptoms, they most often do not eliminate them. Due to the partial beneficial effect of conventional treatments, much effort has been spent in the past years to uncover new and alternative methods to induce antidiuresis in X-NDI patients.

In this regard, the investigators recently reported that statins, in particular fluvastatin, accumulate AQP2 at the apical membrane of collecting duct cells by a AVP-independent mechanism and increase water reabsorption in both wild type and X-NDI mice.