A research team led by Prof. Dr. Thomas Benzing, Director of the Dept. II of Internal Medicine at the University Hospital Cologne and the Center for Molecular Medicine Cologne (CMMC) and CECAD investigator, used ultraresolution microscopy together with mathematical modelling to provide the first experimentally validated model of kidney ultrafiltration. The findings were published in Nature Metabolism - Article | 11 May 2020 as a cover story: The biophysical basis of kidney ultrafiltration - https://www.nature.com/natmetab/
Mammalian kidneys filter large amounts of fluid (about 180 liters in humans every day), with almost complete retention of albumin and other macromolecules in the plasma. Breakdown of the three-layered renal filtration barrier results in loss of albumin into urine (albuminuria) across the wall of small renal capillaries, and is a leading cause of chronic kidney (CKD) In the Western societies. CKD is becoming an increasingly prevalent condition affecting almost 10% of the population. The loss of filtration function causes high blood pressure, predisposes to serious cardiovascular disease, stroke and dementia, and can even lead to the need for dialysis. Despite decades of intensive research the function of the complex renal filtration barrier has remained elusive.
The research group of Thomas Benzing has now succeeded in clarifying the function of the kidney filter and showed that the permeability of the renal filter is modulated through compression of the capillary wall. The research team collect morphometric data prior to and after onset of albuminuria in a mouse model equivalent to a human genetic disease. This model was generated with CRISPR-based genome engineering. Combining quantitative analyses with mathematical modelling, they were able to demonstrate that morphological alterations of the glomerular filtration barrier lead to reduced compressive forces that counteract filtration pressure, thereby resulting in capillary dilatation, and ultimately albuminuria. The results reveal distinct functions of the different layers of the filtration barrier and expand the molecular understanding of defective renal filtration in chronic kidney disease.
Linus Butt, the first author of the study, states: "We are all very excited about the progress that was made. The story is the result of a real team effort and I am very proud to be part of the team." The current study was made possible through international cooperation between scientists of Benzing's research group at the CECAD institute and research groups from Boston, Stockholm and Regensburg. Benzing comments: "We were surprised by the outcome of the study. The study represents a quantum leap in our understanding of the development of kidney diseases. I am convinced that these results will help in the development of better therapies for kidney diseases." The physician-scientist Benzing is an world-renowned expert in molecular mechanisms of kidney diseases.
A molecular mechanism explaining albuminuria in kidney disease
Linus Butt, David Unnersjö-Jess, Martin Höhne, Aurelie Edwards, Julia Binz-Lotter, Dervla Reilly, Robert Hahnfeldt, Vera Ziegler, Katharina Fremter, Markus M. Rinschen, Martin Helmstädter, Lena K. Ebert, Hayo Castrop, Matthias J. Hackl, Gerd Walz, Paul T. Brinkkoetter, Max C. Liebau, Kálmán Tory, Peter F. Hoyer, Bodo B. Beck, Hjalmar Brismar, Hans Blom, Bernhard Schermer and Thomas Benzing
Modified press release of the Center for Molecular Medicine Cologne, Dr. Debora Grosskopf-Kroiher (https://www.cmmc-uni-koeln.de).
Prof. Dr. Thomas Benzing, MD, FASN
Professor and Chairman, Department II of Internal Medicine,
University Hospital of Cologne,
Director, Center for Molecular Medicine Cologne,
Deputy Chair, Excellence Cluster CECAD,
Dr. Sibylle Grandel