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Abstract: PO1832

The Impact of rs2254524 LSS Polymorphism on Blood Pressure in a New Mouse Model

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Faienza, Sipontina, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Citterio, Lorena, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Zagato, Laura, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Messaggio, Elisabetta, 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 salt intake is associated with hypertension (HTN) and shows great variability among individuals. Endogenous ouabain (EO) is a steroid hormone previously associated with HTN. To dissect EO and HTN link at genetic level, we identified as a propensity factor the missense variation rs2254524 (Val642Leu; V642: CC variant; L642: AA variant) in the Lanosterol Synthase (LSS), a key enzyme in steroid biosynthesis.
In patients, the LSS A variant influences the BP and circulating EO level in response to a low salt diet. Moreover, high EO levels were detected in LSS AA kidneys and are associated with a faster decline in GFR in hypertensives.
We hypothesized that LSS affects salt-sensitive HTN by regulation of EO biosynthesis.

Methods

We generated a knock-in mouse model carrying the rs2254524 SNP expression in all tissues. We performed all animal procedures on male mice.
The Blood Pressure was measured by the tail-cuff system, on 5 consequent days in conscious mice, after appropriate training.

Results

LSS AA mice were viable, healthy, and undistinguishable phenotypically from LSS CC.
The LSS transcript and protein levels were slightly reduced in the Adrenal Gland of LSS AA mice at 3 months of age and in the kidney at 6 months of age.
At 3 months of age, EO quantification in LSS AA kidney is about 3.3 pmol/g tissue (SD =1.69) compared to 2.6 pmol/g tissue (SD =1.1) in control.
At baseline, LSS AA mice did not affect SBP and kidney function at 3, 6, and 9 months of age. Nevertheless, we observed an increasing trend in SBP upon High Salt (4% NaCl) diet administration in AA mice, compared to that fed with Control Salt Diet (0.5% NaCl), at 3 months (Fig. 1).

Conclusion

Our preliminary results show that the LSS AA variant affects BP upon high-salt diet administration at 3 months, but further studies are necessary to deepen the effect of LSS A variant on salt-sensitivity at different ages.

Fig. 1: SBP measurement by the tail-cuff system in LSS CC and LSS AA mice upon 4% and 0.5% NaCl diets administration. The first 5 days are considered as training. Bars indicate average ± SEM. *P < 0.05; **P < 0.01

Funding

  • Government Support – Non-U.S.