Hypertension in the (mRen-2)27 Rat Is Not Explained by Enhanced Kinetics of Transgenic Ren-2 Renin

Abstract

Abstract-Enhanced efficiency of the reaction between transgenic Ren-2 mouse renin and endogenous rat angiotensinogen has been suggested as 1 mechanism that contributes to the accelerated hypertension and increased tissue angiotensin of the (mRen-2)27 transgenic rat. This was tested in a study conducted at pH 7.4 in vitro that compared the kinetic constants of purified mouse Ren-2 and rat renin (each at 100, 75, 50, and 25 pmol/L) reacting with physiologic concentrations of rat angiotensinogen (0 to 4 mol/L). Under these conditions, the kinetic constants for Ren-2 (K m , 1.8 mol/L; K cat , 0.07/s; and K cat /K m , 0.04 L · mol Ϫ1 · s Ϫ1 ) were not different from rat renin. However, Ren-2 renin acting on its homologous mouse angiotensinogen was confirmed as being much slower. We conclude that hypertension in the Ren-2 rat is not related to renin kinetics. Other mechanisms are considered, with reference to human essential hypertension. Key Words: renin-angiotensin system Ⅲ angiotensinogen Ⅲ blood pressure Ⅲ hypertension, essential T he hypertensive (mRen-2)27 transgenic rat (Ren-2 rat) developed by Mullins et al 1 displays strong expression of the mouse Ren-2 transgene in several extrarenal tissues, 2 suppressed endogenous renal renin, and predominantly mouse inactive prorenin in the circulation secreted from extrarenal sources. [3][4][5] Most evidence indicates that it is the active component of mouse Ren-2 renin in tissues and plasma, reacting with the endogenous rat angiotensinogen (aogen), that induces and sustains the hypertension through conventional angiotensin II (Ang II)-dependent mechanisms, in particular because the hypertension is readily controlled by inhibition of the renin-angiotensin system (RAS). 6 However, this concept is at odds with the initial published evidence of suppressed or normal active plasma renin and angiotensin peptides in the adult Ren-2 rat, 1,7,8 reports that encouraged a search for additional hypertensive mechanisms. This transgenic rat strain has now been used widely to study various conditions relating to activation of the tissue RAS, including angiogenesis, cytokine activation, and profibrotic and inflammatory pathologic states, making it important to understand fully the fundamental processes inducing the severe hypertension.That plasma Ang II is not suppressed is now apparent, with resting levels increased up to 4-fold in both young 9 and adult 10 Ren-2 rats. One would expect a similar elevation of plasma active renin, but this depends on the pH at which the activity is estimated, 11,12 because mouse and rat renins have different pH optima when acting on rat aogen (pH 8.5 and 6.5, respectively). 5,11,12 Measured at pH 7.4 the Ren-2 rat plasma renin reaction is a mixed activity, mainly owing to the mouse transgenic renin, 11 and increases in renin activity have been found under these physiologic conditions. The lower level of rat renin in plasma is consistent with its low but not absent level in the kidneys. 11,12 By comparison with other high-renin models that cause malignant...

Effects of changes in sodium balance on plasma and kidney angiotensin II levels in anesthetized and conscious Ren-2 transgenic rats

“…Moreover, we and others [8][9][10][11] found that plasma and kidney ANG II levels are not elevated in TGR during the developmental and early phases of hypertension. Finally, it has been reported recently that hypertension in TGR is not related to renin kinetics [12]. Taken together, these results demonstrate that the development of hypertension in TGR could not simply be explained on the basis of increased production of ANG II with subsequent overactivation of AT 1 receptors and, therefore, other mechanisms had to be considered.…”

Blood pressure and renin–angiotensin system resetting in transgenic rats with elevated plasma Val5-angiotensinogen

“…This biochemically determined upper limit would help protect the body from excessive and deleterious Ang II concentrations caused by high Ang-N concentrations. A greater rise in BP has been described only for heterologous mouse renin acting on transgenic rat Ang-N causing abnormally accelerated reaction kinetics [14,29].…”

Circulating versus tissue renin-angiotensin system: On the origin of (pro)renin

“…However, submandibular renin does not enter the circulation in large quantities. Interestingly, Ren2 expression in the rat ([mRen2]27 rat) results in severe hypertension, most likely because mouse Ren2 renin reacts as well with rat angiotensinogen as rat renin does [45].…”