Paul Jennings

Menu_Team Menu_Publications Menu_Pubmed Menu_Google-Scholar Menu_Research-Gate

Renal Epithelial Physiology and Toxicology

 

TeamPJ

From left to right:

Alice Limonciel, Giada Carta, Paul Jennings and Anja Wilmes. (Picture was taken in January 2016 at the System Toxicology Conference in Les Diablerets, Switzerland).

 

Our research: The kidney and susceptibility to injury                


 

Each kidney consists of approximately 1 million nephrons at birth. De novo nephrogenesis does not occur after birth and there is no strong evidence suggesting that the adult kidney harbours resident stem cells. Thus, the kidney unlike the liver is not a highly rejuvenative organ, which is most likely an evolutionary compromise allowing the anatomical complexity required for high function and the maintenance of the very narrow margins required for whole body homeostasis. Indeed, the kidney is an extremely accomplished organ and can carry out 100 % of its duties with only a fraction of the nephrons we are born with. However, we continually lose nephrons through-out life and will, all things being equal, eventually breach the renal functional reserve and enter end-stage-renal disease. Thus, anything that contributes to chronic renal failure has the potential to seriously curtail life quality and life-span. Aging populations and associated risk factors such as diabetes and heart disease, have pushed chronic kidney disease (CKD) incidence to unprecedented levels (currently at 10 % of the European population). Due to the role of the kidney in elimination of waste products, renal cells, particularly the proximal tubule, will internally process the majority of drugs and chemicals, and thus often have higher concentrations of these compounds than any other cell in the body. Compounds that injure renal epithelial cells can initiate and/or accelerate CKD. 

 

The main topics of our research are:

heat-map_small
  • Xenobiotic handling by proximal tubular cells, including uptake, metabolism and extrusion.
  • Integration of omic techniques (transcriptomics, proteomics and metabolomics).
  • Identification of novel mechanistic biomarkers of renal injury.
  • Development of improved systems for chemical safety assessment.
  • The understanding of how cells deal with stress and the delineation of stress response pathways, including oxidative stress (Nrf2), DNA damage (p53), hypoxia (HIF-1alpha) and the unfolded protein response.
  • Claudin expression in the tight junctions of renal epithelial cells, their function and how they are regulated.
  • Differentiation of human induced pluripotent stem cells (iPSC) into renal lineages.
  • Uromodulin biology:  Uromodulin (aka Tamm-Horsfall protein) is the only protein produced exclusively in the kidney and is thought to aid in prevention of renal stones and also to prevent kidney infections.

 

Latest publications:  

2016: Inter-laboratory study of human in vitro toxicogenomics-based tests as alternative methods for evaluating chemical carcinogenicity: a bioinformatics perspective. Herwig, R., Gmuender, H., Corvi, R., Bloch, K.M., Brandenburg, A., Castell, J., Ceelen, L., Chesne, C., Doktorova, T.Y., Jennen, D., Jennings, P., Limonciel, A., Lock, E.A., McMorrow, T., Phrakonkham, P., Radford, R., Slattery, C., Stierum, R., Vilardell, M., Wittenberger, T., Yildirimman, R., Ryan, M., Rogiers, V., and Kleinjans, J. Archives of toxicology 90, 2215-2229 https://www.ncbi.nlm.nih.gov/pubmed/26525393

2016: Development and characterization of a pseudo multiple reaction monitoring method for the quantification of human uromodulin in urine. Hammond, T.G., Moes, S., Youhanna, S., Jennings, P., Devuyst, O., Odermatt, A., and Jeno, P. Bioanalysis 8, 1279-1296 http://www.ncbi.nlm.nih.gov/pubmed/27187191

2016: "Watching the Detectives" report of the general assembly of the EU project DETECTIVE Brussels, 24-25 November 2015. Fernando, R.N., Chaudhari, U., Escher, S.E., Hengstler, J.G., Hescheler, J., Jennings, P., Keun, H.C., Kleinjans, J.C., Kolde, R., Kollipara, L., Kopp-Schneider, A., Limonciel, A., Nemade, H., Nguemo, F., Peterson, H., Prieto, P., Rodrigues, R.M., Sachinidis, A., Schafer, C., Sickmann, A., Spitkovsky, D., Stober, R., van Breda, S.G., van de Water, B., Vivier, M., Zahedi, R.P., Vinken, M., and Rogiers, V. Archives of toxicology 90, 1529-1539 http://www.ncbi.nlm.nih.gov/pubmed/27129694

2016: Improving global feature detectabilities through scan range splitting for untargeted metabolomics by high-performance liquid chromatography-Orbitrap mass spectrometry. Ranninger, C., Schmidt, L.E., Rurik, M., Limonciel, A., Jennings, P., Kohlbacher, O., and Huber, C.G. Anal Chim Acta 930, 13-22 http://www.ncbi.nlm.nih.gov/pubmed/27265900

2016: Moving Beyond Prioritization Toward True In Vitro Safety Assessment. Yoon, M., Adeleye, Y., Clewell, R., Jennings, P., and Whelan, M. Applied In Vitro Toxicology 2, 67-73 http://dx.doi.org/10.1089/aivt.2016.29005.rtl

2016: Ensuring the Quality of Stem Cell-Derived In Vitro Models for Toxicity Testing. Stacey, G.N., Coecke, S., Price, A.B., Healy, L., Jennings, P., Wilmes, A., Pinset, C., Ingelman-Sundberg, M., Louisse, J., Haupt, S., Kidd, D., Robitski, A., Jahnke, H.G., Lemaitre, G., and Myatt, G. Advances in experimental medicine and biology 856, 259-297 http://www.ncbi.nlm.nih.gov/pubmed/27671727

2015: Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Wilmes, A., Bielow, C., Ranninger, C., Bellwon, P., Aschauer, L., Limonciel, A., Chassaigne, H., Kristl, T., Aiche, S., Huber, C.G., Guillou, C., Hewitt, P., Leonard, M.O., Dekant, W., Bois, F., and Jennings, P. Toxicology in vitro : an international journal published in association with BIBRA 30, 117-127 http://www.ncbi.nlm.nih.gov/pubmed/25450742 

 

 >> all publications

 

Congratulations to Anja for winning the 1st Otto-Kraupp-Preis 2017

>> more info here

OKPAnja

 

Paul's Henry Stewart Talk contribution

Jennings, P. (2016), "Molecular basis of genetic renal diseases 1 and 2", in The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at https://hstalks.com/bs/3413/, https://hstalks.com/bs/3414/ )

 

Anja collects her 2016 TWF award for her proposal on claudin regulation in oxidative stress. 

 

TWF-Anja_small

 

https://www.i-med.ac.at/mypoint/news/697115.html

 

Alice wins the CEFIC LRI award 2015 !

 

 

https://www.i-med.ac.at/mypoint/news/696075.html


And the follow up:

 

 

 

 

 Highlighted Articles

 Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel.

Published in Toxiciology and Applied Pharmacology, September 2014.

Claudin2

How water passes through the paracellular space is somewhat of a mystery. In our investigations with nephrotoxic compounds in cultured renal epithelial cells we have discovered that some compounds cause the selective decrease in the expression of specific tight junction proteins for example claudin 2 and claudin 10. In claudin 2 knock down cells we observed an inability of the cells to reabsorb water, but only when cultured on microporous filters. Our explanation is that an osmotic gradient in the paracellular space drives water through tight junctions, but only if claudin 2 is present. Thus claudin 2 is a putative paracellular water channel.  Download article here.  

 

 Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress

 Published in the Journal of Proteomics in January 2013. 

samples

Scheme (top) and CsA induced Cyclophiln B secretion (bottom).

In this paper we investigate the effects of therapeutic and supra theraputic concentrations of the immunosupressive compound  Cyclosporine A (CsA) on cultured human renal proximal tubule cells. We utilised a high content non-biased omic strategy to identify altered transcripts, proteins and metabolites. In addition, together with our collegues in Würtzburg University and Université de Technologie de Compiègne we developed a kinetic model of CsA cell uptake. The paper is the first of its kind to integrate omic technologies to identify compound induced cell stress. It is likely that pharmacological and toxicological screening in the future will employ similar strategies of human cell based systems, integrated omics and biokinetics. Download full open access article  here.

 

 

 

Our Book Contributions


 

Precictiv-toxicology Clin-nephrotoxins-3rd-ed Wiley

 

Our research in the public domain


 

Alice Hase   
  • Alice Limonciel in Die Presse: Den Nierengiften auf der Spur. [Link]
  • Biomarkers for Nephrotoxicity: Putting Data into Functional Context. Lydia Aschauers interview with IPA. [Link]
  • Alice Limonciel and Lydia Aschauer win the 2013 young scientist Lush prize [ Lush ]  
  • Neue Möglichkeiten der Zellforshung dank Nobelpreistechnologie [ My Point ]
  • Guter Ersatz für Tierversuche. [ Die Presse 2012 ]
  • Weg vom Tierversuch [ download pdf ]
  • Biomarken zur Toxitärsprüfung auf der Spur [ My Point ]
  • Neue Tests für krebserregende Chemikalien [ My Point ]
  • Wenn ein alter Freund zum Gegner wird [ My Point ]

 

Left: Alice Limonicel receives the Lush young scientist prize in London, 2013.

 

Projects


 

MSCA-ITN, in3, "An integrated interdisciplinary approach to animal-free nanomaterial and chemical safety assessment." NOW RECRUITING !
Horizon 2020, EU-ToxRisk, "An Integrated European ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st Century"
EU 7th Framework and EFPIA, StemBANCC "Stem cells for Biological Assays of Novel drugs and predictive toxiCology "
EU 7th Framework and Cosmetics Europe, DETECTIVE "Detection of endpoints and biomarkers for repeated dose toxicity using in vitro systems "

 

     EU-ToxRisk-Logo---JPEG    in3logo

 

Recently Completed Projects

 
The NC3R Nephrotube  - "Development of a multi-compartmental, microfluidic tissue model of tubular injury in assays of nephrotoxicity." 
EU 7th Framework, Predict-IV "Profiling the toxicity of new drugs: a non animal-based approach integrating toxico-dynamics and biokinetics "
EU 6th Framework, carcinoGENOMICS "Novel alternative method approaches in carcinogenicity and mutagenicity."

 

  

 

 Renal Logo

Paul Jennings
Division of Physiology,
Dept. Physiology and Medical Physics,
Medical University of Innsbruck,
Schöpfstraße 41/1,
Austria 6020.
Phone: +43 512 9003 70826
paul.jennings@i-med.ac.at

 in3logo

Now recruiting for the new project MSCA-ITN, in3, "An integrated interdisciplinary approach to animal-free nanomaterial and chemical safety assessment." Coordinated by Paul Jennings. See estiv.org/in3 for more details.

 Replacement, refinement and reduction of animal experiments in biomedical research lecture series. Starts Friday November 13th.  
Contact Paul for registration and details.

 

bubbles

Alice gets her bubbles picture on the cover of EMBO. [Link] 

© Medizinische Universität Innsbruck - Alle Rechte vorbehaltenMail an i-master - Letzte Änderung: 20.6.2017, 14:09:41ximsTwitter LogoFacebook Logo