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Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss-of-function mutations in either PKD1 or PKD2 genes, which encode polycystin-1 (TRPP1) and polycystin-2 (TRPP2), respectively. Increased activity of the mammalian target of rapamycin (mTOR) pathway has been shown in PKD1 mutants but is less documented for PKD2 mutants. Clinical trials using mTOR inhibitors were disappointing, while the AMP-activated kinase (AMPK) activator, metformin is not yet tested in patients. Here, we studied the mTOR activity and its upstream pathways in several human and mouse renal cell models with either siRNA or stable knockdown and with overexpression of TRPP2. Our data reveal for the first time differences between TRPP1 and TRPP2 deficiency. In contrast to TRPP1 deficiency, TRPP2-deficient cells did neither display excessive activation of the mTOR-kinase complex nor inhibition of AMPK activity, while ERK1/2 and Akt activity were similarly affected among TRPP1- and TRPP2-deficient cells. Furthermore, cell proliferation was more pronounced in TRPP1 than in TRPP2-deficient cells. Interestingly, combining low concentrations of rapamycin and metformin was more effective for inhibiting mTOR complex 1 activity in TRPP1-deficient cells than either drug alone. Our results demonstrate a synergistic effect of a combination of low concentrations of drugs suppressing the increased mTOR activity in TRPP1-deficient cells. This novel insight can be exploited in future clinical trials to optimize the efficiency and avoiding side effects of drugs in the treatment of ADPKD patients with PKD1 mutations. Furthermore, as TRPP2 deficiency by itself did not affect mTOR signaling, this may underlie the differences in phenotype, and genetic testing has to be considered for selecting patients for the ongoing trials.

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Abbreviations

ADPKD:

Autosomal dominant polycystic kidney disease

AMPK:

AMP-activated protein kinase

[Ca2+]c :

Free Ca2+ concentration in the cytosol

CaMKKβ:

Ca2+/calmodulin-dependent protein kinase kinase-β

CD13:

Aminopeptidase N

ciPTEC:

Conditionally immortalized proximal-tubule epithelial cell

ECL:

Enhanced-chemiluminescence

ESRD:

End-stage renal disease

FACS:

Fluorescence-activated cell sorting

FITC:

Fluoresceinisothiocyanate

KD:

Knockdown

mTOR:

Mammalian target of rapamycin

TRPP1:

Polycystin-1

TRPP2:

Polycystin-2

P-AMPK:

Phosphorylated AMP-activated protein kinase

PKD1:

Gene for TRPP1

PKD2:

Gene for TRPP2

P-S6Rp:

Phosphorylated S6 ribosomal protein

P-S6Rp/Tot S6Rp:

Phosphorylated S6 ribosomal protein/total S6 ribosomal protein

PVDF:

Polyvinylidene fluoride

S6Rp:

S6 ribosomal protein

siRNA:

Small interfering RNA

STO609:

7-oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic acid-acetic acid

TBS:

Tris-buffered saline

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Acknowledgments

This work was supported by grant G0A/09/012 of the Concerted Actions Program of the Research Council of the KU Leuven, grant G.0B13.13 from the Research Foundation Flanders and Clinical PhD fellowship of the Research Foundation Flanders (1700613N0). The authors are grateful for the excellent technical assistance by Tomas Luyten. The authors thank Marina Crabbé, Anja Florizoone, Sandra Van Aerschot, and Inge Bongaers for their help with the cell cultures; Dr. Kathleen Claes, Dr. Bert Bammens, and Dr. Björn Meijers from the University Hospital of Leuven, Belgium for including patients; and Dr. Y. Cai and Dr. S. Somlo, Yale University (New Haven, CT) for sending the TRPP2−/− and TRPP2+/− renal proximal-tubule epithelial cells.

Competing interests

The authors declare that there are no competing interests.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O&N I, Leuven, Belgium

    Djalila Mekahli, Jean-Paul Decuypere, Eva Sammels, Kirsten Welkenhuyzen, Geert Bultynck, Jan B. Parys, Ludwig Missiaen & Humbert De Smedt

  2. Department of Pediatric Nephrology, University Hospital of Leuven, Herestraat 49, 3000, Leuven, Belgium

    Djalila Mekahli & Elena Levtchenko

  3. Laboratory of Pediatrics, KU Leuven, Campus Gasthuisberg O&N I, Leuven, Belgium

    Joost Schoeber, Lambertus van den Heuvel & Elena Levtchenko

  4. Laboratoire de Génétique Moléculaire, CHU - INSERM U613, Brest, France

    Marie-Pierre Audrezet

  5. Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, Campus Gasthuisberg O&N I, Leuven, Belgium

    Anniek Corvelyn

  6. Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris, France

    Georges Dechênes

  7. Academic Unit of Nephrology, University of Sheffield, Sheffield, UK

    Albert C. M. Ong

  8. Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Martijn J. Wilmer & Lambertus van den Heuvel

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  1. Djalila Mekahli
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Correspondence to Djalila Mekahli.

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Djalila Mekahli and Jean-Paul Decuypere shared first co-authorship.

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ESM Fig. 1

Representative analysis of a ciPTEC line (10.064) from an ADPKD patient by flow cytometry. Cells were examined for the presence of the proximal tubular marker CD13 (aminopeptidase N) by flow cytometry. Readings were initially made in unstained cells, then in CD13-FITC-treated cells. (TIFF 77 kb)

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(JPEG 35 kb)

ESM Fig. 2

Representative analysis by RT-PCR for Aquaporin-1 (Aq1) and P-glycoprotein (Pgp) expression in different ciPTEC lines from ADPKD patients as compared with control ciPTEC (positive control). (TIFF 135 kb)

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(JPEG 42 kb)

ESM Fig. 3

mTORC1 activity after siRNA TRPP1-KD and siRNA TRPP2-KD in ciPTEC control cells (34.8). The siRNA data are compared with an siRNA scrambled control. a Representative immunoblot of TRPP1 and TRPP2 expression in siRNA TRPP1-KD, siRNA TRPP2-KD and siRNA scrambled controls (n = 4). b Representative immunoblot of mTORC1 activity assessed by the ratio P-S6Rp/Tot S6Rp (n = 4). The lower panels show the quantification of the data presented as means ± SEM. The values of the siRNA scrambled control cells were set at 100 %. The means were compared using a Student's t test for paired data: *p < 0.05. NS not significant. (TIFF 61 kb)

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Mekahli, D., Decuypere, JP., Sammels, E. et al. Polycystin-1 but not polycystin-2 deficiency causes upregulation of the mTOR pathway and can be synergistically targeted with rapamycin and metformin. Pflugers Arch - Eur J Physiol 466, 1591–1604 (2014). https://doi.org/10.1007/s00424-013-1394-x

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