Clinical and Experimental Nephrology

, Volume 16, Issue 4, pp 539–548 | Cite as

Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis

  • Ayako Sato
  • Hoglan Piao
  • Yukiko Nozawa
  • Tetsuo Morioka
  • Hiroshi Kawachi
  • Takashi Oite
Original Article

Abstract

Background

Increasing evidence indicates that locally blocking renin–angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN.

Methods

Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system.

Results

Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS + aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels.

Conclusion

This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis.

Keywords

Progressive glomerulosclerosis Direct renin inhibitor Local drug delivery Local renin–angiotensin system Renoprotection 

Notes

Acknowledgments

This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan (B: no. 15390266, C: no. 12671032, JSPS; 15/03138, to T.O., and a grant-in-aid for young scientists B: no. 17790548 to J.M.) as well as grants from Novartis Pharmaceuticals and Nippon Shinyaku Co., Ltd.

References

  1. 1.
    Prieto-Carrasquero MC, Kobori H, Ozawa Y, Gutierrez A, Seth D, Navar LG. AT1 receptor-mediated enhancement of collecting duct rennin in angiotensin II-dependent hypertensive rats. Am J Physiol Renal Physiol. 2005;289:F632–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Zhang Z, Shahinfar S, Keane WF, Ramjit D, Dickson TZ, Gleim GW, et al. Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. J Am Soc Nephrol. 2005;16:1775–80.Google Scholar
  3. 3.
    Campbell R, Sangalli F, Perticucci E, Aros C, Viscarra C, Perna A, et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int. 2003;63:1094–103.PubMedCrossRefGoogle Scholar
  4. 4.
    Remuzzi G, Ruggenenti P, Perna A, Dimitrov BD, de Zeeuw D, Hille DA, et al. Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results. J Am Soc Nephrol. 2004;15:3117–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Dechow C, Morath C, Peters J, Lehrke I, Waldherr R, Haxsen V, et al. Effects of all-trans retinoic acid on renin–angiotensin system in rats with experimental nephritis. Am J Physiol Renal Physiol. 2001;281:909–19.Google Scholar
  6. 6.
    Ballermann BJ, Skorecki KL, Brenner BM. Reduced glomerular angiotensin II receptor density in early untreated diabetes mellitus in the rat. Am J Physiol. 1984;247:110–6.Google Scholar
  7. 7.
    Wilkes BM. Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism. Endocrinology. 1987;120:1291–8.PubMedCrossRefGoogle Scholar
  8. 8.
    O’Brien RC, Cooper ME, Jerums G, Doyle AE. The effects of perindopril and triple therapy in a normotensive model of diabetic nephropathy. Diabetes. 1993;42:604–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Mahmood J, Khan F, Okada S, Kumagai N, Morioka T, Oite T. Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis. Kidney Int. 2006;70:1591–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Azizi M, Menard J. Combined blockade of the renin–angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation. 2004;109:2492–9.Google Scholar
  11. 11.
    Mooser V, Nussberger J, Jullierat L. Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition. J Cardiovasc Pharmacol. 1990;15:276–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Orikasa M, Matsui K, Oite T, Shimizu F. Massive proteinuria induced in rats by a single intravenous injection of a monoclonal antibody. J Immunol. 1988;141:807–14.PubMedGoogle Scholar
  13. 13.
    Raij L, Azar S, Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 1984;26:137–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Oyanagi-Tanaka Y, Yao J, Wada Y, Morioka T, Suzuki Y, Gejyo F, et al. Real-time observation of hemodynamic changes in glomerular aneurysms induced by anti-Thy-1 antibody. Kidney Int. 2001;59:252–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Wada Y, Morioka T, Oyanagi-Tanaka Y, Yao J, Suzuki Y, Gejyo F, et al. Impairment of vascular regeneration precedes progressive glomerulosclerosis in anti-Thy-1 glomerulonephritis. Kidney Int. 2002;61:432–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Kawamura K, Okada S, Li B, Suwa M, Yao J, Morioka T, Gejyo F, et al. Turbulence of glomerular hemodynamics involved in progressive glomerulosclerosis. Kidney Int. 2006;69:1792–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Jeunemaitre X, Menard J, Nussberger J, Guyene TT, Brunner HR, Corvol P. Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients. Am J Hypertens. 1989;2:819–27.PubMedGoogle Scholar
  18. 18.
    Rahuel J, Rasetti V, Maibaum J, Rueqer H, Goschke R, Cohen NC, et al. Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol. 2007;7:493–504.CrossRefGoogle Scholar
  19. 19.
    Gradman AH, Schimieder RE, Lins RL, Nussberqer J, Chianq Y, Bediqian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005;111:1012–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Dietz R, Dechend R, Yu CM, Bheda M, Ford J, Prescott MF, et al. Effects of the direct rennin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension. J Renin Angiotensin Aldosterone Syst. 2008;9:163–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Parving HH, Person F, Lewis JB, Hollenberg NK. AVOID Study Investigators: aliskiren combined with losartan in type II diabetes and nephropathy. N Engl J Med. 2008;358:2433–46.PubMedCrossRefGoogle Scholar
  22. 22.
    Salomon SD, Appelbaum E, Manning WJ, Verma A, Berqlund T, Lukashevich V, Aliskiren in Left Ventricular Hypertrophy (ALLAY) Trial Investigators, et al. Effect of the direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertrophy. Circulation. 2009;119:530–7.Google Scholar
  23. 23.
    Trimarchi H. Role of aliskiren in blood pressure control and renoprotection. Int J Nephrol Renovasc Dis. 2011;4:41–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Wood JM, Mailbaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V, et al. Structure-based design of aliskiren, a novel orally effective rennin inhibitor. Biochem Biophys Res Commun. 2003;308:698–705.PubMedCrossRefGoogle Scholar
  25. 25.
    Zou L-X, Imig JD, Von Thun AM, Hymel A, Ono H, Navar LG. Receptor-mediated intrarenal angiotensin II augmentation in angiotensin II-infused rats. Hypertension 1996;28:669–77.Google Scholar
  26. 26.
    Kobori H, Prieto-Carrasquero MC, Ozawa Y, Navar LG. AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension. Hypertension. 2004;43:1126–32.PubMedCrossRefGoogle Scholar
  27. 27.
    Feldman DL, Jin L, Xuan H, Contrepas A, Zhou Y, Webb RL, et al. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension. 2008;52:130–6Google Scholar
  28. 28.
    Fischer NDL, Danser AHJ, Nussberger J, Dole WP, Hollenberg NK. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation. 2008;117:3199–205.CrossRefGoogle Scholar
  29. 29.
    Apperloo AJ, de Zeeuw D, de Jong PE. A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function. Kidney Int. 1997;51:793–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Weier MR. Acute fall in glomerular filtration rate with renin–angiotensin system inhibition: a biomeasure of therapeutic success? Kidney Int. 2011;80:235–7.Google Scholar
  31. 31.
    Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hilleqe HJ, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011;80:282–7.PubMedCrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2012

Authors and Affiliations

  • Ayako Sato
    • 1
    • 4
  • Hoglan Piao
    • 1
  • Yukiko Nozawa
    • 1
  • Tetsuo Morioka
    • 1
  • Hiroshi Kawachi
    • 2
  • Takashi Oite
    • 1
    • 3
  1. 1.Department of Cellular Physiology, Institute of Nephrology, Graduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
  2. 2.Department of Cellular Biology, Institute of Nephrology, Graduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
  3. 3.Department of Clinical Engineering and Medical TechnologyNiigata University of Health and WelfareNiigataJapan
  4. 4.Department of Laboratory MedicineNational Center Hospital of Neurology and PsychiatryTokyoJapan

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