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Abstract: SA-PO754

Salt Sensitivity Is Modulated by Lanosterol Synthase rs2254524 Polymorphism

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms

Authors

  • Faienza, Sipontina, Universita Vita Salute San Raffaele, Milano, Lombardia, Italy
  • Citterio, Lorena, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Messaggio, Elisabetta, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Zagato, Laura, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Lanzani, Chiara, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Simonini, Marco, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Manunta, Paolo, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy

Group or Team Name

  • Genomics of Renal Diseases and Hypertension Unit
Background

The blood pressure (BP) response to different salt intakes, the so-called salt sensitivity, is more frequent in hypertensive patients compared to the general population. Elevated levels of the steroid hormone Endogenous Ouabain (EO) have been associated with hypertension (HT) and salt sensitivity. We characterized the missense variation rs2254524 (Val642Leu; V642: C variant; L642: A variant) of the Lanosterol Synthase (Lss), a gene coding for a key enzyme in steroid biosynthesis, since 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.

Methods

We generated a knock-in mouse model carrying the Lss rs2254524 SNP expression ubiquitously to test our hypothesis. Male mice were fed with a Normal Salt Diet (NSD; 0.5% NaCl), High Salt Diet (HSD; 4% NaCl), or Low Salt Diet (LSD; 0.03 % Na) for 15 days and BP was measured by the BP-2000 Blood Pressure tail-cuff system, in conscious trained mice.

Results

Lss AA mice were viable, healthy, and undistinguishable phenotypically from the WT Lss CC. However, the Lss mRNA and protein levels were reduced in the adrenal glands of mutated mice at 3 months and in the kidneys at 6 months of age, whereas no differences were observed at 12 months of age.
At baseline, the Lss AA polymorphism affected kidney weight, normalized to body weight, that was significantly enlarged at 3 and 12 months of age, compared to its WT counterpart. Moreover, the Systolic BP (SBP) in Lss WT mice showed a progressive increase at 9 and 12 months of age that was not observed in Lss AA mice.
At 3 months, only the AA mice showed a significant SBP reduction after LSD compared to NSD, and upon HSD was observed an SBP increase in AA, but not in CC mice, just at 12 months of age. Moreover, the 12 months mice in HSD showed cardiac hypertrophy, a common feature in hypertensive patients.

Conclusion

Extensive studies are still ongoing, but the new Lss mouse model resembles the salt-sensitive HT together with heart hypertrophy observed in hypertensive patients and provides a good model to prove our hypothesis.

Funding

  • Government Support – Non-U.S.