Renin inhibition ameliorates renal damage through prominent suppression of both angiotensin I and II in human renin angiotensinogen transgenic mice with high salt loading
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The renin–angiotensin–aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.
Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.
High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.
Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.
KeywordsAliskiren Hypertension RAAS Tsukuba hypertensive mouse Renin Angiotensin
- 11.Fukamizu A, Sugimura K, Takimoto E, Sugiyama F, Seo MS, Takahashi S, Hatae T, Kajiwara N, Yagami K, Murakami K. Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J Biol Chem. 1993;268:11617–21.PubMedGoogle Scholar
- 13.Suzuki H, Okada K, Abe M, Maruyama N, Yoshida Y, Baba S, Takashima H, Soma M. Aliskiren reduces home blood pressure and albuminuria in patients with hypertensive nephrosclerosis. Clin Exp Nephrol 2013;17:386–395.Google Scholar
- 15.Pilz B, Shagdarsuren E, Wellner M, Fiebeler A, Dechend R, Gratze P, Meiners S, Feldman DL, Webb RL, Garrelds IM, Jan Danser AH, Luft FC, Müller DN. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension. 2005;46:569–76.PubMedCrossRefGoogle Scholar
- 18.Rakusan D, Kujal P, Kramer HJ, Husková Z, Vanourková Z, Vernerová Z, Mrázová I, Thumová M, Cervenka L, Vanecková I. Persistent antihypertensive effect of aliskiren is accompanied by reduced proteinuria and normalization of glomerular area in Ren-2 transgenic rats. Am J Physiol Renal Physiol. 2010;299:F758–66.PubMedGoogle Scholar
- 27.Feldman DL, Jin L, Xuan H, Contrepas A, Zhou Y, Webb RL, Mueller DN, Feldt S, Cumin F, Maniara W, Persohn E, Schuetz H, Jan Danser a H, Nguyen G. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension. 2008;52:130–6.PubMedCrossRefGoogle Scholar