#1463 Assessment of salt-sensitive hypertension in a novel Lanosterol Synthase knock-in mouse model

Abstract

Abstract Background and Aims The diversity in blood pressure (BP) response to various salt intakes, known as Salt Sensitivity (SS), exhibits significant differences among individuals within the hypertensive subjects relative to the general population. Hypertension (HT) and SS are correlated to elevated levels of plasma Endogenous Ouabain (EO). We aimed at delineating the role of the missense variation rs2254524 (Val642Leu; C>A) within the Lanosterol Synthase gene (LSS), encoding for an enzyme involved in steroid biosynthesis. Individuals with the AA LSS variant, adherent to a low-salt diet, had a more significant BP reduction compared to those with CC genotype. Method Utilising CRISPR-Cas9, we established a knock-in mouse model carrying the analogous LssV643L/V643L. Male mice were subjected to a normal-salt diet (0.5% NaCl), high-salt diet (4% NaCl), or low-salt diet (<0.03% Na) and BP was monitored every two days using a tail-cuff system for 10 days. Blood and urine were collected separately in metabolic cages. Results Homozygous mice for Lss mutation demonstrated normal viability and healthy phenotype, undistinguishable from the WT. At baseline, the Lss AA mice were affected by a significant augmentation in kidney weight at 3 and 12 months of age, relative to WT. The Lss V643L does not influence EO levels or systolic BP (SBP), specifically at 3 and 12 months, but affects the SBP response to dietary salt. AA mice showed a high SBP in a high-salt diet against control diet at the same time intervals. Moreover, the Lss variant impacted the pressure-natriuresis relationship, with the mutated AA strain showing a less steep curve both in control diet versus the high-salt diet and in control diet versus the low-salt diet, displaying the SS phenotype of the AA mice. The 12-month-old mice in high-salt diet displayed cardiac hypertrophy with the AA genotype exhibiting an elevated prevalence of cardiac fibrosis. The level of Lss mRNA decreased in the adrenal glands in response to a high-salt diet. RNASeq analysis identified distinct patterns in several Slc genes, Cbr2 and Arhgap26 within the kidneys of these mice, in control or high-salt dietary conditions. Conclusion The established LssV643L/V643L mouse model effectively mirrors the SS-HT phenotype. Our findings highlight the significance of the Lss in modulating BP in response to salt stimuli suggesting a potential organ damage pathway requiring further exploration in older mice.