Clinical and Experimental Nephrology

, Volume 18, Issue 4, pp 593–599

Renin inhibition ameliorates renal damage through prominent suppression of both angiotensin I and II in human renin angiotensinogen transgenic mice with high salt loading

  • Shigetaka Yoshida
  • Kenichi Ishizawa
  • Nobuhiro Ayuzawa
  • Kohei Ueda
  • Maki Takeuchi
  • Wakako Kawarazaki
  • Toshiro Fujita
  • Miki Nagase
Original Article
  • 319 Downloads

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Aliskiren Hypertension RAAS Tsukuba hypertensive mouse Renin Angiotensin 

Supplementary material

10157_2013_893_MOESM1_ESM.doc (326 kb)
Supplementary material 1 (DOC 326 kb)

References

  1. 1.
    Rüster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol. 2006;17:2985–91.PubMedCrossRefGoogle Scholar
  2. 2.
    Brewster UC, Setaro JF, Perazella MA. The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci. 2003;326:15–24.PubMedCrossRefGoogle Scholar
  3. 3.
    Kawarazaki H, Ando K, Nagae A, Fujita M, Matsui H, Fujita T. Mineralocorticoid receptor activation contributes to salt-induced hypertension and renal injury in prepubertal Dahl salt-sensitive rats. Nephrol Dial Transpl. 2010;25:2879–89.CrossRefGoogle Scholar
  4. 4.
    Kawarazaki W, Nagase M, Yoshida S, Takeuchi M, Ishizawa K, Ayuzawa N, Ueda K, Fujita T. Angiotensin II- and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation. J Am Soc Nephrol. 2012;23:997–1007.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Nagase M, Matsui H, Shibata S, Gotoda T, Fujita T. Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress. Hypertension. 2007;50:877–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Jafar TH. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data. Ann Intern Med. 2001;135:73.PubMedGoogle Scholar
  7. 7.
    Balamuthusamy S, Srinivasan L, Verma M, Adigopula S, Jalandhara N, Jalandara N, Hathiwala S, Smith E. Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis. Am Heart J. 2008;155:791–805.PubMedCrossRefGoogle Scholar
  8. 8.
    Morganti A, Lonati C. Aliskiren: the first direct renin inhibitor available for clinical use. J Nephrol. 2011;24:541–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Hollenberg NK, Osei SY, Lansang MC, Price DA, Fisher ND. Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man. J Renin Angiotensin Aldosterone Sys. 2001;2:14–8.CrossRefGoogle Scholar
  10. 10.
    Krop M, Garrelds IM, De Bruin a RJ, Van Gool JMG, Fisher NDL, Hollenberg NK, Jan Danser a H. Aliskiren accumulates in renin secretory granules and binds plasma prorenin. Hypertension. 2008;52:1076–83.PubMedCrossRefGoogle Scholar
  11. 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
  12. 12.
    Kai T, Sugimura K, Shimada S, Kurooka A, Takenaka T, Ishikawa K. Enhanced angiotensin II stimulates renal disorders in transgenic Tsukuba hypertensive mice. Blood Press. 1998;7:247–50.PubMedCrossRefGoogle Scholar
  13. 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
  14. 14.
    Parving H–H, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren combined with Losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–46.PubMedCrossRefGoogle Scholar
  15. 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
  16. 16.
    Huang L, Howard CG, Mitchell KD. Chronic direct renin inhibition with aliskiren prevents the development of hypertension in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent hypertension. Am J Med Sci. 2012;344:301–6.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kavvadas P, Weis L, Abed AB, Feldman DL, Dussaule J-C, Chatziantoniou C. Renin inhibition reverses renal disease in transgenic mice by shifting the balance between profibrotic and antifibrotic agents. Hypertension. 2013;61:901–7.PubMedCrossRefGoogle Scholar
  18. 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
  19. 19.
    Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, Fujita T. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J Am Soc Nephrol. 2006;17:3438–46.PubMedCrossRefGoogle Scholar
  20. 20.
    Kobayashi H, Shimamoto K, Moriguchi O, Miyahara M. A sensitive radioimmunoassay for the determination of plasma angiotensin II in human subjects. Jpn Circ J. 1979;43:727–33.PubMedCrossRefGoogle Scholar
  21. 21.
    Yoshida S, Nagase M, Shibata S, Fujita T. Podocyte injury induced by albumin overload in vivo and in vitro: involvement of TGF-beta and p38 MAPK. Nephron Exp Nephrol. 2008;108:e57–68.PubMedCrossRefGoogle Scholar
  22. 22.
    Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, Miyoshi J, Takai Y, Fujita T. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14:1370–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Lambers Heerspink HJ, De Borst MH, Bakker SJL, Navis GJ. Improving the efficacy of RAAS blockade in patients with chronic kidney disease. Nat Rev Nephrol. 2013;9:112–21.PubMedCrossRefGoogle Scholar
  24. 24.
    Sato A, Piao H, Nozawa Y, Morioka T, Kawachi H, Oite T. Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis. Clin Exp Nephrol. 2012;16:539–48.PubMedCrossRefGoogle Scholar
  25. 25.
    Edling O, Bao G, Feelisch M, Unger T, Gohlke P. Moexipril, a new angiotensin-converting enzyme (ACE) inhibitor: pharmacological characterization and comparison with enalapril. J Pharmacol Exp Ther. 1995;275:854–63.PubMedGoogle Scholar
  26. 26.
    Nagase M. Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome. Clin Exp Nephrol. 2010;14:303–14.PubMedCrossRefGoogle Scholar
  27. 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

Copyright information

© Japanese Society of Nephrology 2013

Authors and Affiliations

  • Shigetaka Yoshida
    • 1
  • Kenichi Ishizawa
    • 1
  • Nobuhiro Ayuzawa
    • 1
  • Kohei Ueda
    • 1
  • Maki Takeuchi
    • 1
  • Wakako Kawarazaki
    • 2
  • Toshiro Fujita
    • 2
  • Miki Nagase
    • 1
  1. 1.Department of Nephrology and EndocrinologyThe University of Tokyo Graduate School of MedicineTokyoJapan
  2. 2.Department of Clinical EpigeneticsThe University of Tokyo Research Center for Advanced Science and TechnologyTokyoJapan

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