Steroid biosynthesis and renal excretion in human essential hypertension: association with blood pressure and endogenous ouabain.
BACKGROUND
Endogenous ouabain (EO) has been linked with long-term changes in sodium balance and cardiovascular structure and function. The biosynthesis of EO involves, cholesterol side-chain cleavage (CYP11A1), 3-beta-hydroxysteroid dehydrogenase (HSD3B) with sequential metabolism of pregnenolone and progesterone. Furthermore, the renal excretion of cardiac glycosides is mediated by the organic anion transporter (SLCO4C1) at the basolateral membrane and the P-glycoprotein (PGP) (encoded by MDR1) at the apical membrane of the nephron.


METHODS
Average 24-h ambulatory blood pressures were recorded in 729 untreated essential hypertensives. Aldosterone (Aldo), EO, urinary Na+, and K+ excretions were determined. Single-nucleotide polymorphism (SNP) and haplotype-based association study was performed with a total of 26 informative SNPs.


RESULTS
Plasma EO was significantly directly related to both day (r = 0.131, P < 0.01) and nighttime diastolic blood pressure (DBP) (r = 0.143, P < 0.01), and remained significantly related after correction for confounders (sex, body mass index, age). Genotype analysis for EO levels and daytime DBP gave significant results for CYP11A1 rs11638442 and MDR1 rs1045642 (T/C Ile1145) in which the minor allele tracked with higher EO levels (T/T 210.3 (147-272) vs. C/C 270.7 (193-366) pmol/l, P < 0.001). Association was found between HSD3B1 polymorphisms and/or haplotypes with blood pressure (systolic blood pressure (SBP) 140.3 (11.7) vs. 143.8 (11.2) mm Hg, P < 0.01) and plasma Aldo (P < 0.05). Haplotype-based analyses support the data of SNP analysis.


CONCLUSIONS
Among patients with essential hypertension, cholesterol side-chain cleavage and MDR1 loci are related to circulating EO and DBP, most likely by influencing EO synthesis and transmembrane transport, respectively. In contrast, variants in HSD3B1 are related with SBP probably via Aldo.
Tripodi
Grazia
G
Prassis Sigma-Tau, Research Institute, Milan, Italy.
Citterio
Lorena
L
Kouznetsova
Tatiana
T
Lanzani
Chiara
C
Florio
Monica
M
Modica
Rossana
R
Messaggio
Elisabetta
E
Hamlyn
John M
JM
Zagato
Laura
L
Bianchi
Giuseppe
G
Staessen
Jan A
JA
Manunta
Paolo
P
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010042:Ouabain / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000652:urine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010042:Ouabain; D012964:Sodium; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; D011188:Potassium