SALT SENSITIVITY IS MODULATED BY LANOSTEROL SYNTHASE RS2254524 POLYMORPHISM

Abstract

Objective: The blood pressure (BP) response to different salt intakes (salt sensitivity-SS), shows variability among individuals, with more frequency in hypertensives compared to the general population. Elevated levels of the Endogenous Ouabain (EO) have been associated with hypertension (HT) and SS. We characterized the missense variation rs2254524 (Val642Leu; C>A) of the Lanosterol Synthase gene (LSS) coding for an enzyme in steroid biosynthesis, since AA patients on a low-salt diet showed a greater reduction in BP compared to the LSS CC, with only CC having an increase in plasma EO. We aim at dissecting the functional correlation between LSS polymorphism, EO and SS-HT. Design and method: We generated by CRISPR-Cas9 a knock-in mouse model carrying the Lss V643L (LssV643L/V643L), homologous to V642L. Male mice were fed with a normal-salt diet (0.5% NaCl), high-salt diet (4% NaCl), or low-salt diet (<0.03% Na) and BP was measured every two days by the tail-cuff system. Results: LssV643L/V643L mice were viable, healthy, and undistinguishable phenotypically from WT. At baseline, the Lss AA affected kidney weight that was significantly enlarged at 3 and 12 months of age, compared to WT. The Lss V643L mutation did not affect EO and SBP at 3 and 12 months, per se, but affects SBP responsiveness to salt stimulus. We observed a decreased SBP after 10 days of a low-salt diet and increased SBP upon a high-salt diet only in LssV643L/V643L mice compared to the control diet at 3 and 12 months, respectively. Moreover, 12-month-old mice in high-salt diet showed cardiac hypertrophy, and LssV643L/V643L showed a higher incidence of heart fibrosis. In the adrenal gland of LssV643L/V643L mice, Lss mRNA level was reduced upon high-salt diet. At 12 months, RNASeq analysis of renal differentially expressed genes revealed a different regulation of multiple Slc genes, both in control and high-salt diet, but also of Cbr2, and Arhgap26. Conclusions: The new LssV643L/V643L mouse model resembles the SS-HT phenotype together with EO non-responsiveness observed in HT patients, thus providing a good model of SS-HT. Our results reveal a role of Lss gene in the regulation of BP upon salt stimulus.