SALT SENSITIVITY IS MODULATED BY LANOSTEROL SYNTHASE RS2254524 POLYMORPHISM

Abstract

Objective: The blood pressure (BP) response to different salt intake is associated with hypertension (HT). Elevated levels of the steroid hormone Endogenous Ouabain (EO) have been also associated with HT and salt sensitivity. We characterized the missense variation rs2254524 (V642: CC variant; L642: AA variant) of the Lanosterol Synthase (LSS), a key enzyme in steroid biosynthesis, because AA patients on a low salt diet showed a greater reduction in BP compared to the LSS CC and only CC patients had an increase in plasma EO after the low salt protocol. Hence, we hypothesized that LSS could affect salt-sensitive HT by regulation of EO biosynthesis. Design and method: We generated a knock-in mouse model carrying the variation ubiquitously. Male mice were fed with Normal Salt (NSD; 0.5% NaCl), High Salt (HSD; 4% NaCl) or Low Salt Diet (LSD; 0.03 % Na) for 15 days. BP was measured by the tail-cuff system, on 5 consequent days in conscious trained mice. Results: LSS AA mice were viable, healthy, and undistinguishable phenotypically from LSS CC. The LSS mRNA and protein levels were reduced in the adrenal gland of LSS AA mice at 3 months. At baseline, the LSS did not affect kidney function, while at 9 and 12 months the Systolic BP (SBP) in LSS CC mice showed a progressive increase with age; this increase was not observed in LSS AA mice. At 3 months, we observed an increase in SBP in both genotypes upon HSD compared to those on an NSD, however only the AA mice showed a significant SBP reduction after an LSD (Fig.1). The same response of BP upon HSD has also been observed in AA e CC mice at 12 months but only AA mice showed statistically significant cardiac hypertrophy (Fig. 2), a common feature of hypertensives. Conclusions: The new LSS mouse model resembles what was observed in hypertensive patients and provides a good model to prove our hypothesis. In the perspective of clinical practice, these findings allow the identification of patients whose SBP can seriously benefit from a low salt diet as a lifestyle modification.