High blood pressure in transgenic mice carrying the rat angiotensinogen gene.

Abstract

Transgenic mice were generated by injecting the entire rat angiotensinogen gene into the germline of NMRI mice. The resulting transgenic animals were characterized with respect to hemodynamics, parameters of the renin angiotension system, and expression of the transgene. The transgenic line TGM(rAOGEN)123 developed hypertension with a mean arterial blood pressure of 158 mmHg in males and 132 mmHg in females. In contrast, the transgenic line TGM(rAOGEN)92 was not hypertensive. Rat angiotensinogen was detectable only in plasma of animals of line 123. Total plasma angiotensinogen and plasma angiotensin II concentrations were about three times as high as those of negative control mice. In TGM(rAOGEN)123 the transgene was highly expressed in liver and brain. Transcripts were also detected in heart, kidney and testis. In TGM(rAOGEN)92 the brain was the main expressing organ. In situ hybridization revealed an mRNA distribution in the brain of TGM(rAOGEN)123 similar to the one in rat. In TGM(rAOGEN)92 the expression pattern in the brain was aberrant. These data indicate that overexpression of the angiotensinogen gene in liver and brain leads to the development of hypertension in transgenic mice. The TGM(rAOGEN)123 constitutes a high angiotensin II type of hypertension and may provide a new experimental animal model to study the kinetics and function of the renin angiotensin system.

Redox Control of Renal Function and Hypertension

“…Their kidneys are thickened with hypercellular arterial walls, interstitial fibrosis, inflammation, papillary atrophy, and tubular dilation. Angiotensinogen-overexpression models (transgenic mice expressing the rat angiotensinogen gene alone in the liver and brain, TGM[rAOGEN]123) and (transgenic mice expressing the human angiotensinogen gene alone and treated with human renin bolus, or double transgenic mice expressing both human renin and human angiotensinogen), manifest hypertension (159,375,376). Overexpression of angiotensinogen and elevated levels of Ang II can lead to kidney disease by causing growth, inflammation, and fibrosis.…”

Angiotensinogen 235T Allele “Dosage” Is Associated With Blood Pressure Phenotypes

“…A and D, Systolic blood pressure (SBP); B and E, mean arterial pressure (MAP); C and F, diastolic blood pressure (DBP) (mean values and standard errors are in mm Hg). This possibility was elegantly demonstrated by the establishment of transgenic mice expressing high levels of rat AGT and having elevated blood pressure, 32 by the development of a knock-out model of the angiotensinogen gene, showing a significantly lower blood pressure than wild-type mice 33 and by the development of knock-out/knock-in mice strains harboring 0 to 4 copies of the AGT gene. In these animals, plasma angiotensinogen levels increase progressively from zero in the null animals to 145% of normal in the 3-copy animals, and blood pressure increased significantly and almost linearly at Ϸ8 mm Hg per gene copy.…”

Role of Angiotensin Peptides Precursor in Ethanol Mediated Hepato toxicity: Perspective on Angiotensinogen

“…Published reports also indicate direct relation between AGT and blood pressure. For instance, a highly significant relationship between plasma concentration of AGT and blood pressure in human subjects [44], higher plasma AGT levels in hypertensive subjects and in offspring of hypertensive parents compared against normotensives [44,46], expression of AGT gene in multiple tissues and organs are directly involved in blood pressure regulation [47], Moreover, increase in blood pressure is observed in transgenic animals that over-express AGT gene [45,48,49], while, lowering of blood pressure in AGT gene knockout mice has also been observed [45]. Increasing copy number of AGT up to four copies in mice, causes successive increases in blood pressure [48].…”