Aliskiren, a Human Renin Inhibitor, Ameliorates Cardiac and Renal Damage in Double-Transgenic Rats

Abstract

Abstract-We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202Ϯ4 mm Hg), serum creatinine, and albuminuria (34Ϯ5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115Ϯ6 and 139Ϯ5 mm Hg) and albuminuria (0.4Ϯ0.1 and 1.6Ϯ0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148Ϯ4 mm Hg) and albuminuria (2.1Ϯ0.7 mg per day), low-dose Val reduced BP (182Ϯ3 mm Hg) and albuminuria (24Ϯ3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4Ϯ0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and ␤-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR. Key Words: renin Ⅲ rats, transgenic Ⅲ hypertrophy R enin is the rate-limiting step in the generation of angiotensin II (Ang II). 1 Thus, inhibiting this step reduces Ang II levels. Historically, renin inhibitors have not been clinically successful because of lack of potency or bioavailability. The new nonpeptidic renin inhibitor aliskiren is a potent human renin inhibitor (IC 50 ϭ0.6 nmol/L). 2 Because renin displays species specificity for its substrate, human renin inhibitors cannot be tested efficiently in conventional hypertensive rat models. To circumvent this problem, transgenic rats and mice were developed harboring the human renin and the human angiotensinogen genes. 3,4 Human renin does not effectively cleave rat angiotensinogen, and similarly, rat renin cleaves human angiotensinogen poorly. 5 Consequently, the single transgenic rats and mice (ie, transgenic for either human angiotensinogen or renin) are normotensive. However, when cross-bred, the double transgenic rat (dTGR) offspring develop hypertension with severe organ damage and do not live beyond the seventh or eighth week of age. We extensively studied these animals; the injury features nuclear factor B (NF-B) and activator protein-1 transcription factor activation, upregulation of surface adhesion molecules, cytokines, and the influx of inflammatory cells. 6 ...

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

“…Furthermore, glomerular collagen IV accumulation and renal macrophage and lymphocyte contents were lowered. 71 This paper also showed a reduction in renal cortical Ang I and Ang II levels in aliskiren-treated dTGR, thus documenting an inhibitory effect of this DRI on the intrarenal RAAS. Moreover, Ang I-forming capacity of the sera from these rats was also significantly reduced.…”

“…Recently, Ino and coworkers 76 reported that at a non-BP-lowering dose, aliskiren reduced leukocyte adhesion in a murine vascular injury model. Furthermore, this effect of aliskiren was associated with a reduction in the injury-induced up-regulation of adhesion molecules on the vascular endothelium, pointing toward a possible mechanism for the reductions in inflammatory infiltrates noted above in the kidneys of dTGR 71 and mice. 75 Diabetic nephropathy.…”

“…65 and mouse. 87 The anti-inflammatory effect of aliskiren observed in the kidneys of dTGR 71 and eNOS À/À 75 mice is not a renal-specific effect. Recently, Ino and coworkers 76 reported that at a non-BP-lowering dose, aliskiren reduced leukocyte adhesion in a murine vascular injury model.…”

“…In both the above studies, 71,72 AT 1 receptor blockers were included as positive controls; they were not intended to be comparator agents. These drugs were administered at different dosages and by different routes of administration than aliskiren.…”

“…provide a cellular mechanism (that is, podocyte protection) for the anti-albuminuric effect observed in human beings 84,85 as well as animals. 71,75,[86][87][88] In vivo effects of aliskiren in experimental DN. Transgenic mRen-2 rats with superimposed STZ-induced diabetes develop albuminuria, glomerulosclerosis and tubulo-interstitial fibrosis, 69 similar features as in human DN.…”