Benzing, Thomas | Gather, Malte - C 01 (TP)

Most kidney diseases originate in the glomerulus - the filtration unit of the kidney - largely due to the limited regenerative capacity of glomeruli and the inability of terminally differentiated podocytes to self-renew. Podocytes are specialized epithelial cells that enwrap the glomerular capillaries and form complex interdigitating foot processes. The foot processes are connected by a membrane-like junction known as the slit diaphragm, a highly organized structure approximately 50 nanometers wide. Arranged in a meandering pattern along the capillary surface, slit diaphragms define the filtration slits through which approximately 180 liters of primary urine are filtered daily in humans. 

This extraordinary filtration capacity is driven by a high intraglomerular capillary pressure (~40 mmHg), subjecting podocytes to exceptional mechanical stress. Yet, how podocytes-cells incapable of division or renewal - withstand these forces remains poorly understood. A major obstacle has been the lack of suitable tools to quantitatively assess their biophysical properties under physiological and pathophysiological conditions. 

To address this gap, we bring together complementary expertise in podocyte biology and genetics, nanobiophotonics, and nano/microscale engineering. Our interdisciplinary approach aims to (1) develop innovative tools to systematically characterize how podocyte membrane stiffness and contractility respond to changes in the stiffness of the extracellular matrix, (2) investigate how signaling at the slit diaphragm affects podocyte mechanical behavior, and (3) develop and apply nanoscale tools to measure the mechanical properties of isolated, intact glomeruli ex vivo. Together, these studies will uncover fundamental principles of podocyte biomechanics and generate novel tools to study the mechanical resilience of the glomerular filtration barrier in health and disease. This approach would not be possible outside this tandem project of groups with complementary expertise.

Podocytes in the kidney glomerulus are subjected to enormous physical forces. As these cells cannot self renew, loss of the cells due to detachment is a hallmark of progressive kidney disease. We aim to develop tools to study mechanical resistance of podocytes. It is expected that these tools are vital for future research that aims to prevent podocyte loss and progressive kidney disease.

Although recent scientific progress has provided spectacular insight into the biophysics of glomerular ultrafiltration and the essential role of podocyte counteracting hydrostatic forces at the kidney filtration barrier 2-5, mechanical resistance of these cells is poorly understood. Research into this is not covered in any of the scientific programs funded by the DFG since tools to study podocyte mechanics on a cellular level are lacking. The “Gather Lab” develops nano and micro scale devices that combine light and soft materials; in particular, Elastic resonator interference stress microscopy (ERISM) is a recently developed functional imaging modality for the mapping of cellular forces. The method has been successfully used to monitor cellular force generation, but its application in podocyte research is still in its infancy. Here we team up to develop the technologies required for application to podocyte cells cultures and ex vivo/in vivo use. We will also make our tools available to the wider scientific community. This kind of method development and interdisciplinary research can only be done as a pilot study in the close collaboration of a tandem project.

For more information, please check Prof. Benzing´s research website and Gather Lab. 

• Center for Molecular Medicine Cologne (CMMC)
• Clinic II for Internal Medicine
• CECAD Cologne
• Kidney Research Center - nephrolab cologne
• SFB1403

• Center for Molecular Medicine Cologne (CMMC)
• Humboldt Centre for Nano- and Biophotonics, Institute for Light and Matter, Department of Chemistry and Biochemistry
• CECAD Cologne
• Research Training Group 2591 - Template-designed Organic Electronics (TIDE)