title: Differential gene expression of renin and angiotensinogen in the TGR(mREN-2)27 transgenic rat.
abstract: Transgenic rats carrying the murine Ren-2 gene represent a monogenetic model of hypertension characterized by low plasma renin and high extrarenal expression of the transgene. The hypothesis has been raised that stimulated local reninangiotensin systems may be responsible for the development of hypertension in this model. This study analyzes the effects of the converting enzyme inhibitor lisinopril, which specifically interferes with the renin-angiotensin system, and the direct vasodilator dihydralazine on the renal and extrarenal expression of renin and angiotensinogen. A comparison of gene expression between heterozygous and homozygous transgenic and normal Sprague-Dawley rats was also performed. We demonstrate high sensitivity of blood pressure toward converting enzyme inhibition in transgenic TGR(mREN-2)27 rats. In the kidney, expression of the transgene and the endogenous renin gene increased, suggesting that both are modulated by lisinopril in a similar manner. On the other hand, blood pressure reduction by dihydralazine did not abolish renal renin suppression in transgenic rats, indicating that mechanisms different from direct effects of blood pressure account for renin suppression. Homozygosity for the transgene led to increased Ren-2 expression and higher blood pressure and had opposite effects on angiotensinogen expression compared with heterozygous rats. Cardiac hypertrophy was reduced by lisinopril but not dihydralazine and was positively correlated with cardiac angiotensinogen expression. Increased angiotensin II in the adrenal gland of TGR(mREN-2)27 rats, which overexpresses the transgene, provides evidence that this leads to enhanced generation of tissue angiotensin II. We conclude that expression of the mouse transgene, the endogenous rat renin gene, and the angiotensinogen gene is subject to differential tissue-specific regulation. Reversal of cardiovascular damage with the converting enzyme inhibitor but not dihydralazine suggests that angiotensin II generated locally may be involved in the pathogenesis of hypertension and structural changes in TGR(mREN-2)27 rats.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Bachmann
authors.forename: J
authors.initials: J
authors.lastname: Bachmann
authors.forename: M
authors.initials: M
authors.lastname: Bader
authors.forename: D
authors.initials: D
authors.lastname: Ganten
mesh_terms: D000804:Angiotensin II / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D004078:Dihydralazine / Q000494:pharmacology; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D012260:Ribonucleases / Q000302:isolation & purification; D013045:Species Specificity
chemical_list: D012333:RNA, Messenger; D000804:Angiotensin II; D017706:Lisinopril; D012260:Ribonucleases; D012083:Renin; D004078:Dihydralazine