Skip Navigation



NDT Advance Access published online on October 12, 2005
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfi181
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
21/3/598    most recent
gfi181v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wahl, P. R.
Right arrow Articles by Wüthrich, R. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wahl, P. R.
Right arrow Articles by Wüthrich, R. P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 3, 2005
Accepted September 6, 2005

Original Articles

Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD)

Patricia R. Wahl 1, Andreas L. Serra 2, Michel Le Hir 3, Klaus D. Molle 4, Michael N. Hall 4, and Rudolf P. Wüthrich 2*

1 Physiological Institute, University of Basel, Switzerland
2 Physiological Institute, University of Basel, Switzerland; Division of Nephrology, University Hospital, Zürich, University of Basel, Switzerland
3 Anatomical Institute, University Zürich-Irchel, University of Basel, Switzerland
4 Division of Biochemistry, Biozentrum, University of Basel, Switzerland

* To whom correspondence should be addressed.
Rudolf P. Wüthrich, E-mail: rudolf.wuethrich{at}usz.ch



  Abstract

Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the formation of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We examined the effect of the mTOR inhibitor sirolimus (rapamycin) on renal functional loss and cyst progression in the Han:SPRD rat model of ADPKD.

Methods. Five-week-old male heterozygous cystic (Cy/+) and wild-type normal (+/+) rats were administered sirolimus (2 mg/kg/day) orally through the drinking water for 3 months. The renal function was monitored throughout the treatment phase, and rats were sacrificed thereafter. Kidneys were analysed histomorphometrically, and for the expression and phosphorylation of S6K, a well-characterized target of mTOR in the regulation of cell growth.

Results. The steady increase in BUN and creatinine in Cy/+ rats was reduced by 39 and 34%, respectively with sirolimus after 3 months treatment. Kidney weight and 2-kidney/total body weight (2K/TBW) ratios were reduced by 34 and 26% in sirolimus-treated Cy/+ rats. Cyst volume density was also reduced by 18%. Of importance, Cy/+ rats displayed enhanced levels of total and phosphorylated S6K. Sirolimus effectively reduced total and phosphorylated levels of S6K.

Conclusion. We conclude that oral sirolimus markedly delays the loss of renal function and retards cyst development in Han:SPRD rats with ADPKD. Our data also suggest that activation of the S6K signalling pathway plays an important role in the pathogenesis of PKD. Sirolimus could be a useful drug to retard progressive renal failure in patients with ADPKD.

Keywords: ADPKD; Han:SPRD rats; mTOR; rapamycin; sirolimus; S6K.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Renal Physiol.Home page
M. Wu, A. Arcaro, Z. Varga, A. Vogetseder, M. Le Hir, R. P. Wuthrich, and A. L. Serra
Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease
Am J Physiol Renal Physiol, December 1, 2009; 297(6): F1597 - F1605.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
A. L. Serra, A. D. Kistler, D. Poster, F. Krauer, O. Senn, S. Raina, I. Pavik, K. Rentsch, A. Regeniter, D. Weishaupt, et al.
Safety and tolerability of sirolimus treatment in patients with autosomal dominant polycystic kidney disease
Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3334 - 3342.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
I. Zafar, F. A. Belibi, Z. He, and C. L. Edelstein
Long-term rapamycin therapy in the Han:SPRD rat model of polycystic kidney disease (PKD)
Nephrol. Dial. Transplant., August 1, 2009; 24(8): 2349 - 2353.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
D.-C. Fischer, U. Jacoby, L. Pape, C. J. Ward, E. Kuwertz-Broeking, C. Renken, H. Nizze, U. Querfeld, B. Rudolph, D. E. Mueller-Wiefel, et al.
Activation of the AKT/mTOR pathway in autosomal recessive polycystic kidney disease (ARPKD)
Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1819 - 1827.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
G. Distefano, M. Boca, I. Rowe, C. Wodarczyk, L. Ma, K. B. Piontek, G. G. Germino, P. P. Pandolfi, and A. Boletta
Polycystin-1 Regulates Extracellular Signal-Regulated Kinase-Dependent Phosphorylation of Tuberin To Control Cell Size through mTOR and Its Downstream Effectors S6K and 4EBP1
Mol. Cell. Biol., May 1, 2009; 29(9): 2359 - 2371.
[Abstract] [Full Text] [PDF]

Home page
 NDT PlusHome page
R. Peces, C. Peces, V. Perez-Duenas, E. Cuesta-Lopez, S. Azorin, and R. Selgas
Rapamycin reduces kidney volume and delays the loss of renal function in a patient with autosomal-dominant polycystic kidney disease
NDT Plus, April 1, 2009; 2(2): 133 - 135.
[Abstract] [Full Text] [PDF]

Home page
 Cleveland Clinic Journal of MedicineHome page
W. E. BRAUN
Autosomal dominant polycystic kidney disease: Emerging concepts of pathogenesis and new treatments
Cleveland Clinic Journal of Medicine, February 1, 2009; 76(2): 97 - 104.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
S. J. Leuenroth, N. Bencivenga, P. Igarashi, S. Somlo, and C. M. Crews
Triptolide Reduces Cystogenesis in a Model of ADPKD
J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1659 - 1662.
[Abstract] [Full Text] [PDF]

Home page
 CJASNHome page
C. L. Edelstein
Mammalian Target of Rapamycin and Caspase Inhibitors in Polycystic Kidney Disease
Clin. J. Am. Soc. Nephrol., July 1, 2008; 3(4): 1219 - 1226.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
C. C. Berthier, P. R. Wahl, M. L. Hir, H.-P. Marti, U. Wagner, H. Rehrauer, R. P. Wuthrich, and A. L. Serra
Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease
Nephrol. Dial. Transplant., March 1, 2008; 23(3): 880 - 889.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
Q. Qian, H. Du, B. F. King, S. Kumar, P. G. Dean, F. G. Cosio, and V. E. Torres
Sirolimus Reduces Polycystic Liver Volume in ADPKD Patients
J. Am. Soc. Nephrol., March 1, 2008; 19(3): 631 - 638.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
T. Weimbs
Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1
Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1423 - F1432.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
E. W. Kuehn and G. Walz
Prime time for polycystic kidney disease: does one shot of roscovitine bring the cure?
Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2133 - 2135.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
C. R. Amura, K. S. Brodsky, R. Groff, V. H. Gattone, N. F. Voelkel, and R. B. Doctor
VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice
Am J Physiol Cell Physiol, July 1, 2007; 293(1): C419 - C428.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
A. B. Chapman
Autosomal Dominant Polycystic Kidney Disease: Time for a Change?
J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1399 - 1407.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
W. M. Bernhardt, M. S. Wiesener, A. Weidemann, R. Schmitt, W. Weichert, P. Lechler, V. Campean, A. C. M. Ong, C. Willam, N. Gretz, et al.
Involvement of Hypoxia-Inducible Transcription Factors in Polycystic Kidney Disease
Am. J. Pathol., March 1, 2007; 170(3): 830 - 842.
[Abstract] [Full Text] [PDF]

Home page
 QJMHome page
J. Rapoport
Autosomal dominant polycystic kidney disease: pathophysiology and treatment
QJM, January 1, 2007; 100(1): 1 - 9.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
V. E. Torres
Water for ADPKD? Probably, Yes
J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2089 - 2091.
[Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.