Podocyte signaling and glomerular biology

Chronic kidney disease (CKD) is becoming an increasingly prevalent condition affecting almost 10% of the population in the Western societies. The majority of kidney diseases that progress to CKD start in the glomerulus, the renal filtration unit, as a consequence of a very limited capacity of glomeruli for regeneration and the limited ability of terminally differentiated glomerular podocytes for self-renewal. Postmitotic podocytes are essential components of the three-layered glomerular filtration barrier of the kidney, and we have demonstrated that podocyte function is regulated through signalling at a highly specialized cell junction, called the slit diaphragm. Over the past decade my team has pioneered the concept that podocytes are master regulators of the glomerular microcirculation/filtration. Using methods of advanced molecular biology and phosphoproteomics as well as genetically engineered animals we deciphered signalling networks that are controlled through slit diaphragm associated protein complexes and showed that these signalling networks are essential for podocyte viability and function and the physiology of kidney filtration. Moreover, we showed that podocytes are acutely mechanosensitive through mechanisms involving the ion channel TRPC6 and the PHB-domain protein Podocin. Our work greatly benefits from insight derived in the model organisms C. elegans, Drosophila melanogaster as well as genetically engineered mice. 

 
 
 
 
 
 
 
 

In the fly eye, slit diaphragm associated proteins control morphogenesis and cell fate decisions very similarly to the situation in mammalian kidney podocytes. In C. elegans touch neurons, MEC-2 (a Podocin ortholog) is required for channel mechanosensitivity leading to the exciting idea that evolutionarily conserved mechanisms contribute to a newly described mechanosensor in the kidney. Studies that involved the nematode system revealed a role for lipid interactions at the channel complex in mechanosensation and identified new components of the megadalton lipid-protein supercomplexes of Podocin/MEC-2 and the associated ion channels. In mice, we developed technologies to visualize glomerular function and podocyte biology in living animals in real time using multiphoton microscopy studies. Taken together, work in my team has initiated a new field of research that will ultimately change our view of glomerular filtration, the regulation of kidney function and our understanding of renal disease. Our group interacts with investigators worldwide including groups at Harvard Medical School, MIT, Stanford University, UCLA, Washington University and Karolinska Institute among others. The research team is closely connected to our clinical department that I am chairing and that is affiliated with a large clinical research unit. Here we aim for translation of the findings in the lab to new treatment options in patients suffering from kidney disease. The group greatly benefits from close interactions at the Cluster of Excellence on Cellular Stress Responses in Aging Associated Diseases (CECAD) and the Center for Molecular Medicine Cologne (CMMC) as well as the Systems Biology of Ageing network (Sybacol).

Group Leader

Prof. Dr. Thomas Benzing

Teammembers

  • Linus Butt, MD
  • Karim Heinlein
  • Ingo Plagmann, MD
  • Dervla Reilly

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.