Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats

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 ( 202 +/- 4 mm Hg), serum creatinine, and albuminuria ( 34 +/- 5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP ( 115 +/- 6 and 139 +/- 5 mm Hg) and albuminuria ( 0.4 +/- 0.1 and 1.6 +/- 0.6 mg per day) and normalized serum creatinine. Although high- dose Val lowered BP ( 148 +/- 4 mm Hg) and albuminuria ( 2.1 +/- 0.7 mg per day), low- dose Val reduced BP ( 182 +/- 3 mm Hg) and albuminuria ( 24 +/- 3.8 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 ( 4.4 +/- 0.1 mg/ g), increased left ventricular ( LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and beta- 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.