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Endothelial Gata5 transcription factor regulates blood pressure.

Messaoudi S, He Y, Gutsol A, Wight A, Hébert RL, Vilmundarson RO, Makrigiannis AP, Chalmers J, Hamet P, Tremblay J, McPherson R, Stewart AF, Touyz RM, Nemer M - Nat Commun (2015)

Bottom Line: Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP).Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways.Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.

ABSTRACT
Despite its high prevalence and economic burden, the aetiology of human hypertension remains incompletely understood. Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP). GATA5 is expressed in microvascular endothelial cells and its genetic inactivation in mice (Gata5-) leads to vascular endothelial dysfunction and hypertension. Endothelial-specific inactivation of Gata5 mimics the hypertensive phenotype of the Gata5- mice, suggestive of an important role for GATA5 in endothelial homeostasis. Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways. Consistent with a role in human hypertension, we report genetic association of variants at the GATA5 locus with hypertension traits in two large independent cohorts. Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension.

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Gata5- mice have features of human essential hypertension.(a) Gata5- mice are salt sensitive: adult mice were fed either a high-salt diet (HSD, 8% NaCl) for 6 weeks or low-salt diet (LSD, 0.02% NaCl) for 10 days. HSD increased BP in Gata5- mice, while LSD decreased it. A regular salt diet (RSD, 0.5% NaCl) for 4 weeks brought BP to its baseline (n=4 per group). The results are reported as mean±s.e.m. ***P<0.005 versus corresponding Gata5+/+ mice; #P<0.05 versus Gata5+/+ mice fed with RSD (repeated measures two-factor ANOVA test followed by Bonferonni correction for multiple comparisons). (b) Increased perivascular fibrotic area to vessel diameter ratio (PFA/VD) in old Gata5- mice. Sections are stained with Masson's Trichrome (scale bar, 100 μm; n=5–7 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (c,d) Kidney dysfunction in 12-months-old Gata5- mice is characterized by decreased glomerular filtration rate (GFR) and increased urinary protein excretion (n=5–6 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (e) Periodic acid Schiff (PAS) staining showing significant alterations of glomerular structure in old Gata5- mice (scale bar, 30 μm; n=5–7 per group). Quantification is on the right. The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test). (f) Significant increase in inflammatory cells infiltration in Gata5- mice kidneys as assessed by CD45 (leucocytes) immunostaining (scale bar, 200 μm; n=5–7 per group). The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test).
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f6: Gata5- mice have features of human essential hypertension.(a) Gata5- mice are salt sensitive: adult mice were fed either a high-salt diet (HSD, 8% NaCl) for 6 weeks or low-salt diet (LSD, 0.02% NaCl) for 10 days. HSD increased BP in Gata5- mice, while LSD decreased it. A regular salt diet (RSD, 0.5% NaCl) for 4 weeks brought BP to its baseline (n=4 per group). The results are reported as mean±s.e.m. ***P<0.005 versus corresponding Gata5+/+ mice; #P<0.05 versus Gata5+/+ mice fed with RSD (repeated measures two-factor ANOVA test followed by Bonferonni correction for multiple comparisons). (b) Increased perivascular fibrotic area to vessel diameter ratio (PFA/VD) in old Gata5- mice. Sections are stained with Masson's Trichrome (scale bar, 100 μm; n=5–7 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (c,d) Kidney dysfunction in 12-months-old Gata5- mice is characterized by decreased glomerular filtration rate (GFR) and increased urinary protein excretion (n=5–6 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (e) Periodic acid Schiff (PAS) staining showing significant alterations of glomerular structure in old Gata5- mice (scale bar, 30 μm; n=5–7 per group). Quantification is on the right. The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test). (f) Significant increase in inflammatory cells infiltration in Gata5- mice kidneys as assessed by CD45 (leucocytes) immunostaining (scale bar, 200 μm; n=5–7 per group). The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test).

Mentions: Later stages of hypertension are generally associated with salt sensitivity and target-organ damage, in particular the heart and kidney18. We tested whether the evolution of hypertension in Gata5- mice follows the natural history of human hypertension. A high-salt diet (8% NaCl) increased BP in 8-month-old Gata5- mice, while a low-salt diet (0.025% NaCl) decreased it, without normalizing it (Fig. 6a). Regular salt diet for 4 weeks after the end of high- or low-salt diet treatment brought BP back to its initial level. Thus Gata5- mice develop salt sensitivity with age. The older Gata5- mice (on a regular salt diet) also developed cardiac perivascular fibrosis (Fig. 6b) and several features of hypertensive nephropathy with increased proteinuria and decreased glomerular filtration rate (Fig. 6c,d). Histology revealed segmental glomerulosclerosis with mesangial cell proliferation, glomerular basement membrane thickening and accumulation of extracellular matrix (Fig. 6e). Similarly, inflammatory (Et1, Ccl2, Ccl5 and Pai1) and kidney injury (Havcr1) markers (Supplementary Fig. 10) as well as inflammatory cell infiltration were also increased in these older animals (Fig. 6f). The Gata5- mice represent, therefore, a new model of systemic hypertension that reproduces several of the features found in hypertensive patients.


Endothelial Gata5 transcription factor regulates blood pressure.

Messaoudi S, He Y, Gutsol A, Wight A, Hébert RL, Vilmundarson RO, Makrigiannis AP, Chalmers J, Hamet P, Tremblay J, McPherson R, Stewart AF, Touyz RM, Nemer M - Nat Commun (2015)

Gata5- mice have features of human essential hypertension.(a) Gata5- mice are salt sensitive: adult mice were fed either a high-salt diet (HSD, 8% NaCl) for 6 weeks or low-salt diet (LSD, 0.02% NaCl) for 10 days. HSD increased BP in Gata5- mice, while LSD decreased it. A regular salt diet (RSD, 0.5% NaCl) for 4 weeks brought BP to its baseline (n=4 per group). The results are reported as mean±s.e.m. ***P<0.005 versus corresponding Gata5+/+ mice; #P<0.05 versus Gata5+/+ mice fed with RSD (repeated measures two-factor ANOVA test followed by Bonferonni correction for multiple comparisons). (b) Increased perivascular fibrotic area to vessel diameter ratio (PFA/VD) in old Gata5- mice. Sections are stained with Masson's Trichrome (scale bar, 100 μm; n=5–7 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (c,d) Kidney dysfunction in 12-months-old Gata5- mice is characterized by decreased glomerular filtration rate (GFR) and increased urinary protein excretion (n=5–6 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (e) Periodic acid Schiff (PAS) staining showing significant alterations of glomerular structure in old Gata5- mice (scale bar, 30 μm; n=5–7 per group). Quantification is on the right. The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test). (f) Significant increase in inflammatory cells infiltration in Gata5- mice kidneys as assessed by CD45 (leucocytes) immunostaining (scale bar, 200 μm; n=5–7 per group). The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test).
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f6: Gata5- mice have features of human essential hypertension.(a) Gata5- mice are salt sensitive: adult mice were fed either a high-salt diet (HSD, 8% NaCl) for 6 weeks or low-salt diet (LSD, 0.02% NaCl) for 10 days. HSD increased BP in Gata5- mice, while LSD decreased it. A regular salt diet (RSD, 0.5% NaCl) for 4 weeks brought BP to its baseline (n=4 per group). The results are reported as mean±s.e.m. ***P<0.005 versus corresponding Gata5+/+ mice; #P<0.05 versus Gata5+/+ mice fed with RSD (repeated measures two-factor ANOVA test followed by Bonferonni correction for multiple comparisons). (b) Increased perivascular fibrotic area to vessel diameter ratio (PFA/VD) in old Gata5- mice. Sections are stained with Masson's Trichrome (scale bar, 100 μm; n=5–7 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (c,d) Kidney dysfunction in 12-months-old Gata5- mice is characterized by decreased glomerular filtration rate (GFR) and increased urinary protein excretion (n=5–6 per group). The results are reported as mean±s.e.m. *P<0.05 versus Gata5+/+ mice (t-test). (e) Periodic acid Schiff (PAS) staining showing significant alterations of glomerular structure in old Gata5- mice (scale bar, 30 μm; n=5–7 per group). Quantification is on the right. The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test). (f) Significant increase in inflammatory cells infiltration in Gata5- mice kidneys as assessed by CD45 (leucocytes) immunostaining (scale bar, 200 μm; n=5–7 per group). The results are reported as mean±s.e.m. ***P<0.005 versus Gata5+/+ mice (t-test).
Mentions: Later stages of hypertension are generally associated with salt sensitivity and target-organ damage, in particular the heart and kidney18. We tested whether the evolution of hypertension in Gata5- mice follows the natural history of human hypertension. A high-salt diet (8% NaCl) increased BP in 8-month-old Gata5- mice, while a low-salt diet (0.025% NaCl) decreased it, without normalizing it (Fig. 6a). Regular salt diet for 4 weeks after the end of high- or low-salt diet treatment brought BP back to its initial level. Thus Gata5- mice develop salt sensitivity with age. The older Gata5- mice (on a regular salt diet) also developed cardiac perivascular fibrosis (Fig. 6b) and several features of hypertensive nephropathy with increased proteinuria and decreased glomerular filtration rate (Fig. 6c,d). Histology revealed segmental glomerulosclerosis with mesangial cell proliferation, glomerular basement membrane thickening and accumulation of extracellular matrix (Fig. 6e). Similarly, inflammatory (Et1, Ccl2, Ccl5 and Pai1) and kidney injury (Havcr1) markers (Supplementary Fig. 10) as well as inflammatory cell infiltration were also increased in these older animals (Fig. 6f). The Gata5- mice represent, therefore, a new model of systemic hypertension that reproduces several of the features found in hypertensive patients.

Bottom Line: Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP).Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways.Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.

ABSTRACT
Despite its high prevalence and economic burden, the aetiology of human hypertension remains incompletely understood. Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP). GATA5 is expressed in microvascular endothelial cells and its genetic inactivation in mice (Gata5-) leads to vascular endothelial dysfunction and hypertension. Endothelial-specific inactivation of Gata5 mimics the hypertensive phenotype of the Gata5- mice, suggestive of an important role for GATA5 in endothelial homeostasis. Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways. Consistent with a role in human hypertension, we report genetic association of variants at the GATA5 locus with hypertension traits in two large independent cohorts. Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension.

Show MeSH
Related in: MedlinePlus