Blood Pressure–Independent Effects in Rats With Human Renin and Angiotensinogen Genes

Abstract

Abstract-The blood pressure-independent effects of angiotensin II (Ang II) were examined in double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes, in which the end-organ damage is due to the human components of the renin angiotensin system. Triple-drug therapy (hydralazine 80 mg/L, reserpine 5 mg/L, and hydrochlorothiazide 25 mg/L in drinking water) was started immediately after weaning. Triple-drug therapy normalized blood pressure and coronary resistance, only partially prevented cardiac hypertrophy, and had no effect on ratio of renal weight to body weight. Although triple-drug therapy delayed the onset of renal damage, severe albuminuria nevertheless occurred. Semiquantitative scoring of ED-1-positive and MIB-5-positive (nuclear cell proliferation-associated antigen Ki-67) cells showed profound perivascular monocyte/macrophage infiltration and cell proliferation in kidneys and hearts of untreated dTGR. Triple-drug therapy had only a minimal effect on local inflammatory response or vascular cell proliferation. In contrast, a novel orally active human renin inhibitor (HRI), 30 mg/kg by gavage for 4 weeks, normalized blood pressure and coronary resistance and also prevented cardiac hypertrophy and albuminuria. ED-1-positive cells and MIB-5-positive cells were decreased by HRI in hearts and kidneys almost to levels observed in normotensive Sprague-Dawley rats. The renoprotective effects of HRI were at least in part due to improved renal hemodynamics and distal tubular function, since HRI shifted renal pressure-diuresis/natriuresis curves leftward by Ϸ35 mm Hg, increased glomerular filtration rate and renal blood flow, and shifted the fractional water and sodium excretion curves leftward. In untreated dTGR, plasma Ang II was increased by 400% and renal Ang II level was increased by 300% compared with Sprague-Dawley rats. HRI decreased plasma human renin activity by 95% and normalized Ang II levels in both plasma and kidney compared with triple-drug therapy. Our findings indicate that in dTGR harboring human renin and angiotensinogen genes, Ang II causes end-organ damage and promotes inflammatory response and cellular growth largely independent of blood pressure. (Hypertension. 2000;35:587-594.)Key Words: renin Ⅲ angiotensinogen Ⅲ angiotensin II Ⅲ albuminuria Ⅲ cell proliferation Ⅲ natriuresis A sscher and Anson 1 demonstrated a vascular permeability factor causing arterial necrosis in malignant hypertension. Subsequently, other investigators reported similar findings and presented evidence that angiotensin II (Ang II) was responsible. [2][3][4] More recent studies indicated that Ang II can be synthesized not only in the blood compartment but also locally in the tissues. 5 Furthermore, alternative pathways to the angiotensin-converting enzyme may exist for local Ang II generation. 6,7 Ang II acts as a direct trophic factor for smooth muscle cells and cardiac myocytes in vitro. 8,9 The effects are mediated through the AT 1 receptor and involve activation of signal transduction pathways...

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

“…The activated RAAS in these animals leads to severe hypertension with renal damage, including albuminuria, elevated serum creatinine, renal infiltration of macrophages, and ECM deposition. 68,70 In this model, aliskiren (0.3 or 3 mg kg -1 per day) normalized the BP and reversed existing renal damage, evidenced by normalizing albuminuria and serum creatinine levels. Furthermore, glomerular collagen IV accumulation and renal macrophage and lymphocyte contents were lowered.…”

“…These studies showed the efficacy of aliskiren in high Ang II-induced renal injury and suggested a beneficial effect of the drug in complement-dependent renal disease. Notably, an earlier study of dTGR showed that when the renin inhibitor remikiren and a non-RAAS blocking anti-hypertensive therapy were compared at comparable BP-lowering doses, remikiren showed stronger renoprotection, 70 suggesting BP-independent effects of renin inhibition.…”

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

“…Angiotensinconverting enzyme inhibitors, alone or in combination with AT 1 R blockers, have been shown to decrease urine protein excretion, even in normotensive subjects and independent of blood pressure. 2,30 In diabetic subjects whose aldosterone levels increased during angiotensin-converting enzyme inhibition, the addition of an aldosterone blocker decreased urinary protein even further, without any changes in blood pressure. 31 In our studies, the decrease in urinary protein excretion by AT 1 R AS-ODN occurred in WKY and SHR, but the decrease in protein excretion was greater in SHR such that it was no longer different from that seen in AS-ODN-treated WKY.…”

“…G enetic manipulations that increase the activity of the renin-angiotensin system (RAS) systemically [1][2][3][4][5] or in specific organs (eg, brain and kidney) elevate blood pressure. 6,7 For example, overexpression of angiotensinogen and renin in renal proximal tubules 6 or in neurons and glia cells in brain 7 increased blood pressure without increasing circulating renin levels.…”

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

“…Ang II concentrations in the circulation and in tissues are about fivefold higher in dTGR compared to non-transgenic SD controls. 27,33 We have previously shown that myocardial, renal, and vascular damage in dTGR are age-dependent. In fact, immediately after weaning at age 3 to 4 weeks, myocardial and renal tissue morphology by light microscopy are indistinguishable between dTGR and normotensive SD rats.…”