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      Activation of Calcium-Sensing Receptor increases intracellular calcium and decreases cAMP and mTOR in PKD1 deficient cells

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          Abstract

          Clinical and fundamental research suggest that altered calcium and cAMP signaling might be the most proximal events in ADPKD pathogenesis. Cells from ADPKD cysts have a reduced resting cytosolic calcium [Ca 2+] i and increased cAMP levels. CaSR plays an essential role in regulating calcium homeostasis. Its activation is associated with [Ca 2+] i increase and cAMP decrease, making CaSR a possible therapeutic target. Human conditionally immortalized Proximal Tubular Epithelial cells (ciPTEC) with stable knockdown of PKD1 (ciPTEC-PC1KD) and ciPTEC generated from an ADPKD1 patient (ciPTEC-PC1Pt) were used as experimental tools. CaSR functional expression was confirmed by studies showing that the calcimimetic NPS-R568 induced a significant increase in [Ca 2+] i in ciPTEC-PC1KD and ciPTEC-PC1Pt. Resting [Ca 2+] i were significantly lower in ciPTEC-PC1KD with respect to ciPTECwt, confirming calcium dysregulation. As in native cyst cells, significantly higher cAMP levels and mTOR activity were found in ciPTEC-PC1KD compared to ciPTECwt. Of note, NPS-R568 treatment significantly reduced intracellular cAMP and mTOR activity in ciPTEC-PC1KD and ciPTEC-PC1Pt. To conclude, we demonstrated that selective CaSR activation in human ciPTEC carrying PKD1 mutation increases [Ca 2+] i, reduces intracellular cAMP and mTOR activity, reversing the principal dysregulations considered the most proximal events in ADPKD pathogenesis, making CaSR a possible candidate as therapeutic target.

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          The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.

          Jonathan Shillingford, Noel Murcia, Claire H. Larson … (2006)
          Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.
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            LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.

            R J Shaw (2009)
            The AMP-activated serine/threonine protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes that is activated under conditions of low intracellular ATP following stresses such as nutrient deprivation or hypoxia. In the past 5 years, work from a large number of laboratories has revealed that one of the major downstream signalling pathways regulated by AMPK is the mammalian target-of-rapamycin [mammalian target of rapamycin (mTOR) pathway]. Interestingly, like AMPK, the mTOR serine/threonine kinase plays key roles not only in growth control and cell proliferation but also in metabolism. Recent work has revealed that across eukaryotes mTOR orthologues are found in two biochemically distinct complexes and only one of those complexes (mTORC1 in mammals) is acutely sensitive to rapamycin and regulated by nutrients and AMPK. Many details of the molecular mechanism by which AMPK inhibits mTORC1 signalling have also been decoded in the past 5 years. AMPK directly phosphorylates at least two proteins to induce rapid suppression of mTORC1 activity, the TSC2 tumour suppressor and the critical mTORC1 binding subunit raptor. Here we explore the molecular connections between AMPK and mTOR signalling pathways and examine the physiological processes in which AMPK regulation of mTOR is critical for growth or metabolic control. The functional conservation of AMPK and TOR in all eukaryotes, and the sequence conservation around the AMPK phosphorylation sites in raptor across all eukaryotes examined suggest that this represents a fundamental cell growth module connecting nutrient status to the cell growth machinery. These findings have broad implications for the control of cell growth by nutrients in a number of cellular and organismal contexts.
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              Defective Glucose Metabolism in Polycystic Kidney Disease Identifies A Novel Therapeutic Paradigm

              Isaline Rowe, Marco Chiaravalli, Valeria Mannella … (2013)
              Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation 1 . Recent identification of signaling cascades de-regulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking 2,3 . Using a metabolomic approach here we identify a pathogenic pathway in ADPKD which can be safely targeted for therapy. We show that mutation in PKD1 results in enhanced glycolysis in cells, in a murine model of PKD, and in human-derived ADPKD kidneys. Glucose deprivation reduced proliferation and sensitized PKD1 mutant cells to apoptosis. Notably, treatment of two distinct PKD mouse models with 2-deoxyglucose (2DG) ameliorates kidney volume, cystic index and reduced proliferation rates. These metabolic alterations depend on the ERK pathway acting in a dual manner by inhibiting the LKB1-AMPK axis on the one hand while activating the mTORC1-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a novel therapeutic paradigm using existing drugs, either individually or in combination.
              Article 0 comments Cited 188 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Annarita Di Mise: annarita.dimise@uniba.it
                Giovanna Valenti: giovanna.valenti@uniba.it
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 9 April 2018
                Publication date PMC-release: 9 April 2018
                Publication date Collection: 2018
                Volume: 8
                Electronic Location Identifier: 5704
                Affiliations
                [1 ]ISNI 0000 0001 0120 3326, GRID grid.7644.1, Department of Biosciences, Biotechnologies and Biopharmaceutics, , University of Bari, ; Bari, 70125 Italy
                [2 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Pediatric Nephrology, , Radboud University Nijmegen Medical Centre, ; Nijmegen, 6525 HP The Netherlands
                [3 ]ISNI 0000 0004 0626 3338, GRID grid.410569.f, Department of Pediatric Nephrology, , University Hospital Gasthuisberg, ; Leuven, 3000 Belgium
                [4 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Department of Development & Regeneration, , University of Leuven (KU Leuven), ; Leuven, 3000 Belgium
                [5 ]ISNI 0000 0004 1758 3396, GRID grid.419691.2, Istituto Nazionale di Biostrutture e Biosistemi, ; Roma, 00136 Italy
                [6 ]ISNI 0000 0001 0120 3326, GRID grid.7644.1, Center of Excellence in Comparative Genomics (CEGBA), , University of Bari, ; Bari, 70125 Italy
                Article
                Publisher ID: 23732
                DOI: 10.1038/s41598-018-23732-5
                PMC ID: 5890283
                PubMed ID: 29632324
                SO-VID: 92cf2a57-64cf-4ed9-b9b0-382370b10318
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 3 October 2017
                Date accepted : 13 March 2018
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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