Response to genetic manipulations of liver angiotensinogen in the physiological range

Abstract

Genetic variation in the human angiotensinogen gene (AGT) influences plasma AGT concentration and susceptibility to essential hypertension by a mechanism that remains to be clarified. When one or two additional copies of the gene were inserted by gene titration (by homologous recombination with gap-repair at the AGT locus), both plasma AGT and arterial pressure were elevated in the physiological range in the mouse. The causal dependency between plasma AGT and blood pressure and the relative contribution of the various tissues that express AGT to these two phenotypic parameters remained to be determined. To address these issues, we generated a transgenic mouse with overexpression of the mouse AGT gene restricted to the liver. The transgene was examined in two contrasted genetic backgrounds, the sodium-sensitive C57BL/6J and the sodium-resistant A/J. Transgenic and control male animals underwent continuous cardiovascular monitoring by telemetry for 14 days while under a standard sodium diet (0.2%). Moderate but significant increases in plasma AGT (40%, p = 0.01) and systolic blood pressure (4-6 mmHg, p ranging from 0.01 to \0.001) were observed in the sodium-sensitive background, but not in the sodium-resistant animals. Statistical analysis of a large number of consecutive, repeated measurements of blood pressure afforded power to detect small effects in the physiological range by use of advanced mixed models of analysis of variances and covariances. Although plasma renin activity was increased in the sodium-sensitive background, it did not reach statistical significance. These observations underline a potential contribution of systemic AGT to the mechanism of AGT-mediated hypertension, but the significance of sodium sensitivity in the genetic background suggests participation of the kidney in expression of the elevated blood pressure phenotype, a matter that will warrant further studies. They also highlight the challenge of identifying the contribution of individual genes in complex inheritance, as their effects are modulated by other genetic and environmental determinants.

Nonmodulation as the Mechanism for Salt Sensitivity of Blood Pressure in Individuals with Hypertension and Type 2 Diabetes Mellitus

“…It is possible that an increase in local AGT levels and altered renal blood flow response, both seen with NMOD status, are contributing to the salt sensitivity observed in our T2DM-HTN population. Recent studies support this explanation, demonstrating a relationship between higher plasma and urinary AGT levels and greater salt sensitivity (38,39). Additional studies are also warranted to determine whether blocking AGT levels via a pharmacological RAAS inhibitor improves the vascular dysfunction, altered renal blood flow response, and salt sensitivity in T2DM, similar to HTN (35).…”

Overexpression of mouse angiotensinogen in renal proximal tubule causes salt-sensitive hypertension in mice

“…20 The mice were allowed to recover for at least 1 week after surgery. Blood pressure, heart rate, and activity were monitored for 10 s every half an hour.…”

“…Analysis of repeated measurement of blood pressure was carried out using SAS software as described previously. 20 Blood pressure was analyzed for daytime and nighttime separately to reduce the effects caused by the heterogeneity in activity during the two periods. A previous study in our laboratory has shown a significant change in variances in the transitions from active to inactive states.…”

“…A previous study in our laboratory has shown a significant change in variances in the transitions from active to inactive states. 20 To reduce the variance and simplify the model, the measurements during the transition of the two activity states were excluded from the analysis. Consequently, daytime was defined as 10:00 am to 5:00 pm and nighttime was defined as 8:00 pm to 5:00 am.…”

A Possible Interaction Between Systemic and Renal Angiotensinogen in the Control of Blood Pressure

“…7,8 Our group developed a model of liver overexpression of mouse AGT using the albumin enhancer promoter; these animals were mildly hypertensive. 9 In addition, we recently demonstrated that overexpression of mouse AGT in PT also causes hypertension. 10 The above studies helped delineate the potential importance of systemic and renal AGT in controlling BP; however one question that has not been fully addressed is whether these two AGT systems can influence one another-that is, do they operate jointly or independently?…”