High Human Renin Hypertension in Transgenic Rats

Abstract

We developed a model of spontaneously high human remn hypertensron m the rat by producing two transgemc strains, one for human angrotensmogen with the endogenous promoter and one for human renm with the endogenous promoter Neither transgemc strain was hypertensive These strains were then crossed, producing a double transgemc strain The double transgemc rats, both males and females, developed severe hypertension (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days If untreated The rats had a human plasma rerun concentratton of 2692381 (+SD) ng angtotensm I (Ang I)/mL per hour, plasma renm actrvrty of 1772176 ng Ang I/mL per hour, rat angtotensmogen concentratron of 1 492 1 pg Ang I/mL, and human angtotensmogen concentration of 78239 pg Ang I/mL (n=49) Control rats had plasma remn actrvrty of 3 7t3.9 ng Ang I/mL per hour and rat angrotensmogen of 1 3220 16 /lg Ang I/mL Angrotensmogen transgene expression by RNase protectton assay was ubrqmtously present but most prominent m liver Renm transgene expression was htgh m kidney but absent m liver The rats featured severe cardiac hypertrophy, with mcreased cross section of cardromyocytes but little myocardtal fibrosts The kidneys showed atrophrc tubules, thickened vessel walls, and increased mterstttmm Both the angtotensm-converting enzyme mhtbttor hsmopnl and the specific human remn mhtbttor remrkrren lowered blood pressure to normal values Double transgemc mice have been developed that exhibit features quite similar to those described here, their gene expressions are stmtlar The spectfictty of rodent and human renm 1s stmrlarly documented Although many elegant physrologtcal studtes can now be done m mice, rats nevertheless offer flexrbdrty, partrcularly m terms of detailed cardiac and renal phystology and pharmacology We conclude that this double transgemc strain wtll facthtate srmultaneous mvesttgatton of genettc and pathophystologtcal aspects of remn-induced hypertension The fact that human renm can be studied m the rat IS a unique feature of this model (Hypertensron. 1997 When infused wrth hREN, this otherwrse normotensrve rat becomes severely hypertensive 1 Under the condrtton of chronic mfusron wrth hREN, the rat is smtable for study of hREN mhtbitors, whrch otherwrse have no effect in the rat.2 However, for study of the human renm-angrotensm system m the rat for perrods ranging from weeks to months, the mimpump mfuston model has maJor shortcommgs, making rt not suitable for studying mechanisms of cardiac hypertrophy, hypertensive nephrosclerosrs, or central nervous system damage To ctrcumvent this problem, we have crossed the TGR(hAOGEN) with a TGR harboring the hREN gene. This TGR(hREN)IOJ was developed m Japan In- Correspondence to Frredrrch C Luft, Franz Volhard Clnuc, Wrltberg Strasse 50, 13122 Berlin, FRG E-marl fcluft@ orton rz mdc-berlm de 0 1997 Amerrcan Heart Assocratron, Inc formation on this rat has not yet been published Offspring from this cross harbor both transgenes and therefore have all the necessary components of the hu...

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