Variable Transcriptional Regulation of the Human Aldosterone Synthase Gene Causes Salt-Dependent High Blood Pressure in Transgenic Mice

Abstract

Background Aldosterone, synthesized in the adrenal cortex by the enzyme CYP11B2, induces positive sodium balance and predisposes to hypertension. Various investigators, using genomic DNA analyses, have linked −344T polymorphism in the hCYP11B2 gene to human hypertension. Human CYP11B2 gene promoter has three SNPs in linkage disequilibrium: T/A at −663, T/C at −470 and C/T at −344. Variants ACT occur together and form the haplotype-I while variants TTC constitute haplotype-II. We hypothesize that these SNPs, when present together, will lead to haplotype-dependent differences in the transcriptional regulation of the hCYP11B2 gene and affect blood pressure regulation. Methods and Results We evaluated differences in tissue expression, in vivo, and consequential effects on blood pressure stemming from the two haplotypes. Novel transgenic (TG) mice with the hCYP11B2 gene, targeted to the mouse HPRT locus, with either haplotype-II or I variant are used in the study. Our results show increased adrenal and renal expression of hCYP11B2 in TG mice with haplotype-I, as compared to mice with haplotype-II. Importantly, we observed increased baseline blood pressure in haplotype-I TG mice, an effect accentuated by a high-salt diet. Pathophysiological impact of elevated aldosterone was corroborated by our results showing up-regulation of proinflammatory markers in renal tissues from the TG mice with haplotype-I. Conclusions These findings characterize haplotype-dependent regulation of the hCYP11B2 gene where −344T serves as a reporter polymorphism and show that haplotype-I leads to increased expression of hCYP11B2, with permissive effects on blood pressure and inflammatory milieu.

Increased renal oxidative stress in salt-sensitive human GRK4γ486V transgenic mice

“…hGRK4γ486V is associated with increased cardiovascular risk (48) but may increase the response to diuretic therapy (49). Only a few gene variants thought to be causal of hypertension in humans have been shown to produce hypertension in mice, e.g., AGT that encodes angiotensinogen (50), AGTR1 that encodes the AT 1 R (51), CYP11B2 that encodes aldosterone synthase (52), and UMOD (53) that encodes uromodulin. However, GRK4 is the only human gene in which the hGRK4γWT transgene is associated with normal BP and salt resistance, the hGRK4γ142V transgene causes salt-resistant hypertension while the hGRK4γ486V causes salt-sensitive hypertension (normal BP on normal sodium diet and high BP on high salt diet) in mice.…”

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

“…These criteria include gene linkage and gene variant association, in vitro phenotype, with the definitive evidence involving the expression of the variant genes in transgenic animals [64, 117]. Only the variants of genes of AGT that encodes angiotensinogen [118], AGTR1 that encodes the angiotensin II (Ang II) type 1 receptor (AT 1 R) [119], CYP11B2 that encodes aldosterone synthase [120], and GRK4 have been shown to cause hypertension in transgenic mice [121, 122]. Variants of ATP2B1, STK39 [123], GRK4, and SLC4A5 [124, 125] have been associated with salt sensitivity; GRK4γ486V causes salt-sensitive hypertension in transgenic mice [126].…”

Gastrorenal Axis

“…Only a few gene variants thought to be causal of hypertension in humans have been shown to produce hypertension in mice, e.g., AGT that encodes angiotensinogen (81), AGTR1 that encodes the AT 1 R (82), CYP11B2 that encodes aldosterone synthase (83), UMOD (84) that encodes uromodulin, and GRK4 (85-90). These genes fulfill the criteria for ascribing a gene as causal of a complex disorder, such as hypertension (91, 92).…”