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01-10-2009 | Original Article

Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats

Authors: Tadashi Okada, Toshifumi Sakaguchi, Ikuji Hatamura, Fumie Saji, Shigeo Negi, Haruhisa Otani, Yasuteru Muragaki, Hiroshi Kawachi, Takashi Shigematsu

Published in: Clinical and Experimental Nephrology | Issue 5/2009

Abstract

Background

Proteinuria caused by glomerular disease is characterized by podocyte injury. Vasopressin V2 receptor antagonists are effective in reducing albuminuria, although their actions on glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of tolvaptan, a selective oral V2 receptor antagonist, on podocytes in a puromycin aminonucleoside (PAN)-induced nephrosis rat model.

Methods

Rats were allocated to a control, PAN nephrosis, or tolvaptan-treated PAN nephrosis group (n = 9 per group). Urinary protein excretion and serum levels of total protein, albumin, creatinine, and total cholesterol were measured on day 10. The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy.

Results

PAN induced massive proteinuria and serum creatinine elevation on day 10, both of which were significantly ameliorated by tolvaptan. Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats. In tolvaptan-treated rats, nephrin and podocin expressions retained their normal linear pattern. Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats.

Conclusions

Tolvaptan is protective against podocyte damage and proteinuria in PAN nephrosis. This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis. Tolvaptan is a promising pharmacological tool in the treatment of renal edema.

Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med. 1998;339:1448–56.CrossRefPubMed

Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest. 2006;116:288–96.CrossRefPubMedPubMedCentral

Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestilä M, Jalanko H, et al. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci USA. 1999;96:7962–7.CrossRefPubMedPubMedCentral

Pavenstädt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83:253–307.CrossRefPubMed

Bankir L, Bouby N, Trinh-Trang-Tan MM. Possible involvement of vasopressin and urine concentrating process in the progression of chronic renal failure. Kidney Int. 1989;27:S32–7.

Bankir L, Bouby N. Vasopressin and urinary concentration: additional risk factors in the progression of chronic renal failure. Am J Kidney Dis. 1991;17:20–6.CrossRefPubMed

Bankir L, Ahloulay M, Bouby N, Trinh-Trang-Tan MM, Machet F, Lacour B, et al. Is the process of urinary urea concentration responsible for a high glomerular filtration rate? J Am Soc Nephrol. 1993;4:1091–103.PubMed

Bardoux P, Bichet DG, Martin H, Gallois Y, Marre M, Arthus MF, et al. Vasopressin increases urinary albumin excretion in rats and humans: involvement of V2 receptors and the renin–angiotensin system. Nephrol Dial Transplant. 2003;18:497–506.CrossRefPubMed

Bardoux P, Bruneval P, Heudes D, Bouby N, Bankir L. Diabetes-induced albuminuria: role of antidiuretic hormone as revealed by chronic V2 receptor antagonism in rats. Nephrol Dial Transplant. 2003;18:1755–63.CrossRefPubMed

10.

Kawachi H, Koike H, Kurihara H, Yaoita E, Orikasa M, Shia MA, et al. Cloning of rat nephrin: expression in developing glomeruli and in proteinuric states. Kidney Int. 2000;57:1949–61.CrossRefPubMed

11.

Kawachi H, Koike H, Kurihara H, Sakai T, Shimizu F. Cloning of rat homologue of podocin: expression in proteinuric states and in developing glomeruli. J Am Soc Nephrol. 2003;14:46–56.CrossRefPubMed

12.

Floege J, Kriz W, Schulze M, Susani M, Kerjaschki D, Mooney A, et al. Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. J Clin Invest. 1995;96:2809–19.CrossRefPubMedPubMedCentral

13.

Pyo HJ, Summer SN, Niederberger M, Kim JK, Schrier RW. Arginine vasopressin gene expression in rats with puromycin-induced nephrotic syndrome. Am J Kidney Dis. 1995;25:58–62.CrossRefPubMed

14.

Wang X, Gattone V 2nd, Harris PC, Torres VE. Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J Am Soc Nephrol. 2005;16:846–51.CrossRefPubMed

15.

Topham PS, Kawachi H, Haydar SA, Chugh S, Addona TA, Charron KB, et al. Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin. J Clin Invest. 1999;104:1559–66.CrossRefPubMedPubMedCentral

16.

Nakatsue T, Koike H, Han GD, Suzuki K, Miyauchi N, Yuan H, et al. Nephrin and podocin dissociate at the onset of proteinuria in experimental membranous nephropathy. Kidney Int. 2005;67:2239–53.CrossRefPubMed

17.

Gross ML, Adamczak M, Rabe T, Harbi NA, Krtil J, Koch A, et al. Beneficial effects of estrogens on indices of renal damage in uninephrectomized SHRsp rats. J Am Soc Nephrol. 2004;15:348–58.CrossRefPubMed

18.

Wartiovaara J, Ofverstedt LG, Khoshnoodi J, Zhang J, Mäkelä E, Sandin S, et al. Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. J Clin Invest. 2004;114:1475–83.CrossRefPubMedPubMedCentral

19.

Terada Y, Tomita K, Nonoguchi H, Yang T, Marumo F. Different localization and regulation of two types of vasopressin receptor messenger RNA in microdissected rat nephron segments using reverse transcription polymerase chain reaction. J Clin Invest. 1993;92:2339–45.CrossRefPubMedPubMedCentral

20.

Schor N, Ichikawa I, Brenner BM. Mechanisms of action of various hormones and vasoactive substances on glomerular ultrafiltration in the rat. Kidney Int. 1981;20:442–51.CrossRefPubMed

21.

Kim JK, Summer SN, Erickson AE, Schrier RW. Role of arginine vasopressin in medullary thick ascending limb on maximal urinary concentration. Am J Physiol. 1986;251:F266–70.PubMed

22.

Bouby N, Ahloulay M, Nsegbe E, Déchaux M, Schmitt F, Bankir L. Vasopressin increases glomerular filtration rate in conscious rats through its antidiuretic action. J Am Soc Nephrol. 1996;7:842–51.PubMed

23.

Bankir L, Kriz W. Adaptation of the kidney to protein intake and to urine concentrating activity: similar consequences in health and CRF. Kidney Int. 1995;47:7–24.CrossRefPubMed

24.

Bardoux P, Martin H, Ahloulay M, Schmitt F, Bouby N, Trinh-Trang-Tan MM, et al. Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: study in vasopressin-deficient Brattleboro rats. Proc Natl Acad Sci USA. 1999;96:10397–420.CrossRefPubMedPubMedCentral

25.

Anderson S, Rennke HG, Brenner BM. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest. 1986;77:1993–2000.CrossRefPubMedPubMedCentral

26.

Hirano T, Yamamura Y, Nakamura S, Onogawa T, Mori T. Effects of the V(2)-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats. J Pharmacol Exp Ther. 2000;292:288–94.PubMed

Title: Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats
Authors: Tadashi Okada
Toshifumi Sakaguchi
Ikuji Hatamura
Fumie Saji
Shigeo Negi
Haruhisa Otani
Yasuteru Muragaki
Hiroshi Kawachi
Takashi Shigematsu
Publication date: 01-10-2009
Publisher: Springer Japan
Published in: Clinical and Experimental Nephrology / Issue 5/2009
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI: https://doi.org/10.1007/s10157-009-0196-0

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Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats

Abstract

Background

Methods

Results

Conclusions

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Abstract

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