Abstract 320: Gata5 Null Mice: A New Genetic Model Of Low-Renin Salt-Sensitive Hypertension
GATA5, a transcription factor of the GATA family, is expressed in the kidney where its function is unknown. In mice, inactivation of GATA5 leads to a cardiac hypertrophy similar to that observed in hypertension. We hypothesized that GATA5 in the kidney may participate in blood pressure (BP) regulation.
Blood pressure was measured by tail-cuff in 3-5 month old GATA5 null (G5-KO) mice and their Wild-type (Wt) littermates. Systolic BP was higher in G5-KO mice when compared to Wt in both males (143±4 vs 122±3 mm Hg, p<0.001, n=14-15) and females (137±2 vs 117±3 mm Hg, p<0.001, n=11-12). High salt diet (8% NaCl for 6 weeks) further increased BP in G5-KO mice (p<0.05) but not in Wt. Under regular diet, there were no changes in water consumption (Wt: 4.0±0.2 ml/24h; vs KO-G5: 4.1±0.1 ml/24h) and urine excretion (Wt: 1.3±0.1 ml/24h; vs KO-G5: 1.1±0.1 ml/24h). Aldosterone urinary concentration was unchanged (Wt: 16.8±2.0 pmol/24h; vs KO-G5: 16.9±1.2 pmol/24h) as well as urinary and plasmatic electrolytes (Na+, K+, Cl-) concentrations. We determined that GATA5 was mainly expressed in the proximal tubule. Expression of genes coding proteins involved in sodium reabsorption in that segment (or others) was either unchanged (NHE3, NKCC2 and aENAC) or decreased (αNaK-ATPase -15% p<0.05; βENaC -21% p<0.01) in G5-KO mice. Renin expression was also decreased by 40% (p<0.05). In contrast, renal expression of pro-inflammatory genes was increased in G5-KO mice (MCP1 +155% p<0.005, PAI1 +90% p<0.01, RANTES +95% p<0.01) but the number of macrophages (assessed by F4/80 immunostaining) in kidney was not different and Masson’s trichrome staining revealed no fibrosis. In contrast, periodic acid Schiff staining showed glomerular hypercellularity in KO-G5 mice (p<0.05). Older G5-KO mice (10 months) exhibited more severe lesions: focal segmental glomerulosclerosis with mesangial cell proliferation, glomerular basement membrane thickening and accumulation of mesangial extracellular matrix.
In summary, G5-KO mice are characterized by hypertension, salt sensitivity and glomerular lesions. They represent a new genetic model to study low-renin hypertension (which affects up to 25% of the hypertensive population) and for which the underlying mechanisms remain incompletely understood.
Author Disclosures: S. Messaoudi: None. A. Gutsol: None. R.L. Hébert: None. M. Nemer: None.
- © 2014 by American Heart Association, Inc.