A novel mouse model recapitulates the effects of rs2254524 variant in the lanosterol synthase gene on salt sensitivity and organ damage

Objective: The blood pressure (BP) response to salt intake (salt sensitivity) shows great variability among individuals and is more frequent in hypertensive patients. Elevated levels of the steroid hormone Endogenous Ouabain (EO) are associated with hypertension (HT) and salt sensitivity. The lanosterol synthase gene (LSS) plays a key role in the biosynthesis of steroids and its rs2254524 variant (Val642Leu) is linked to salt sensitivity in humans. This study aims to investigate the pathophysiological significance of the Lss missense variation in a new knock-in mouse model of salt-sensitive HT onset. Methods: We generated a mouse model carrying the murine homolog (Val643Leu) of the human LSS variant. C57BL/6N LssV643L/V643L were fed different NaCl diets (low-salt, LSD; normal-salt, NSD; high-salt, HSD) and were characterized at functional, histological, and molecular levels. Results: At baseline, mutant mice showed an enlarged kidney compared to the wild-type (WT) counterpart, but the Lss V643L variant did not affect EO biosynthesis nor systolic BP at 3 and 12 months. In HSD, we observed an increased systolic BP only in 12-month-old LssV643L/V643L mice, compared to NSD. Moreover, only the HSD Lss V643L/V643L mice showed cardiac hypertrophy and a higher incidence of cardiac fibrosis compared to WT at 12 months. Finally, the Lss mRNA level was differentially regulated by HSD in the adrenal gland, liver, and heart of LssV643L/V643L mice compared to WT. Conclusions: The novel Lss mouse model resembles the salt-sensitive HT phenotype observed in hypertensive patients and provides a good model of salt-sensitive HT and HT-mediated organ damage.