Deciphering the metabolome at the kidney filtration barrier

Diseases of the kidney filtration barrier are a leading cause of chronic kidney disease and endstage renal failure. The filtration of plasma into primary urine is a highly selective process that takes place in about 1 million filtration units, the glomeruli. The filtration barrier consists of three layers: the fenestrated endothelium of the vasculature, the glomerular basement barrier (GBM) and at the outer aspect of the capillaries, the highly differentiated, glomerular epithelial cell, the podocytes. The latter are solely attached to the GBM and bathed in primary urine. The severity and reversibility of any glomerular disease is defined by the degree of podocyte injury. Loss of podocytes, due to apoptosis or detachment from the glomerular basement membrane, leads to renal/glomerular scarring (Focal Segmental Glomerulosclerosis) and ultimately to the development of kidney failure.

 
 
 
 
 
 
 

Our research work focuses on the function of podocytes in states of health and disease with special emphasis on metabolic pathways. Basic research and translational questions are addressed using state-of-the-art molecular biological methods/technology and various model-organisms including conditional knock-out and transgenic mice, C. elegans and Drosophila melanogaster. We are currently investigating

  1. intercellular signalling cascades that define the unique three-dimensional shape of podocytes. Loss of podocyte cell structure is the final cellular phenotype of any glomerular disease accompanied with loss of protein into the urine. Our research aims to characterize and to understand the signalling pathways required to maintain the delicate cellular architecture of podocytes in states of health and disease.
  2. the role of stress kinases in response to podocyte injury. Here, we primarily focus on the role of the NF-kB signalling cascade and study the role of podocytes as pro-inflammatory cells maintaining the inflammatory micro-milieu and thereby contributing to the glomerular damage.
  3. metabolic pathways in podocytes. Using mouse models and in vitro comparative studies we are trying to trace possible pathways of mitochondria including nucleus cross-communication as well as lipid metabolism that could determine the cell-type specific response in health and disease.
  4. novel therapeutic approaches to treat pre-eclampsia, a medical condition during pregnancy associated with high levels of proteinuria and elevated blood pressure, which may precede life-threatening complications like seizures, stroke and multiorgan failure in the mother with devastating consequences for the fetus. We are participating in clinical studies evaluating novel treatment options and translate our clinical findings into basic research questions.

Group Leader

Prof. Dr. Paul Brinkkötter

Teammembers

  • Henning Hagmann, MD
  • Anja-Maria Klein
  • Sybille Köhler, PhD
  • Angelika Köser
  • Lucas Kühne
  • Vivian Ludwig
  • Mahsa Matin
  • Johanna Odenthal
  • Cem Özel, MD
  • Thomas Schömig
  • Kristina Schönfelder
  • Christina Schroeter

 

Address of this CAP-CMMC group:

Center for Molecular Medicine Cologne
Robert-Koch-Str. 21
50931 Köln, Germany

Selected Publications

  1. Ising, C., Koehler, S., Brahler, S., Merkwirth, C., Hohne, M., Baris, O.R., Hagmann, H., Kann, M., Fabretti, F., Dafinger, C., Bloch, W., Schermer, B., Linkermann, A., Bruning, J.C., Kurschat, C.E., Muller, R.U., Wiesner, R.J., Langer, T., Benzing, T., and Brinkkoetter, P.T. (2015). Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol Med. 7(3): p. 275-87.
  2. Brahler, S., Ising, C., Barrera Aranda, B., Hohne, M., Schermer, B., Benzing, T., and Brinkkoetter, P.T. (2015). The NF-kappaB essential modulator NEMO controls podocyte cytoskeletal dynamics independent of NF-kappaB. Am J Physiol Renal Physiol: p. ajprenal 00059.2015. [Epub ahead of print]
  3. Hagmann, H., Kuczkowski, A., Ruehl, M., Lamkemeyer, T., Brodesser, S., Horke, S., Dryer, S., Schermer, B., Benzing, T., and Brinkkoetter, P.T. (2014). Breaking the chain at the membrane: paraoxonase 2 counteracts lipid peroxidation at the plasma membrane. FASEB J. 28(4): p. 1769-79.
  4. Brinkkoetter, P.T., Ising, C., and Benzing, T. (2013). The role of the podocyte in albumin filtration. Nat Rev Nephrol. 9(6): p. 328-36.
  5. Brinkkoetter, P.T., Olivier, P., Wu, J.S., Henderson, S., Krofft, R.D., Pippin, J.W., Hockenbery, D., Roberts, J.M., and Shankland, S.J. (2009). Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells. J Clin Invest. 119(10): p. 3089-101.