Professor Thomas Benzing

Organisation / Institute
Department II of Internal Medicine
University Hospital Cologne

Address

Prof. Thomas Benzing
Department II of Internal Medicine,
Nephrology, Rheumatology, Diabetes
and General Internal Medicine
Kerpener Str. 62
50859 Köln, Germany

thomas.benzing[at]uk-koeln.de

B. Role of stress signaling in podocytes in progressive damage of the glomerular microcirculation

Professor Thomas Benzing

Rationale and aims

Chronic kidney disease (CKD) is an increasingly prevalent condition and associated with cardiovascular morbidity and mortality. Microvascular dysfunction of the glomerular circulation is of major importance in the pathogenesis of CKD, as the majority of kidney diseases start in the glomerular microcirculation of the kidney filter. Loss of podocytes, pericyte-like cells of the glomerular capillaries, is now being viewed as the culprit of progressive glomerular disease as postmitotic podocytes display a very limited capacity of self-renewal. Research over the past decade has revealed that activation of pathogenic pathways in podocytes is both sufficient and required for the development of progressive glomerular disease and damage to the glomerular microcirculation.

Current state of research and own preliminary work

Recently, we showed that intrinsic stress signaling pathways and overshooting inflammatory signaling in podocytes promote glomerular disease. Furthermore, inhibition of podocyte inflammatory signaling by podocyte-specific gene deletion of the NF-kB essential modulator (NEMO, IKBKG) gene alleviated glomerular inflammatory disease and prevented dysfunction of the glomerular microcirculation. We also used advanced mass spectrometry based proteomics technologies to show that inflammatory changes of the podocyte are associated with profound changes in proteostasis mechanisms involving the ubiquitin-proteasome system as well as proteolytic processing through intracellular proteases.

Experimental approach and work program

In this project, we will now further define the underlying molecular and cellular mechanisms that may contribute to progressive damage of the glomerular microvasculature due to inflammatory signaling in podocytes. The major aim is to develop a profound understanding of the signaling mechanisms and consequences on protein homeostasis in podocytes to develop options to resolve intracellular stress damage. Specifically, we will (1) identify the targets of proinflammatory signaling in cleavage of cytoskeletal and slit diaphragm proteins, (2) assess the contribution of stress signaling in podocyte cell detachment from the underlying basement membrane resulting in denudation of capillaries, and (3) study the contribution of various stress signaling pathways to podocyte apoptosis, necrosis, and detachment using advanced live-imaging technologies. In collaboration with the Pasparakis and Brüning groups, we have already generated various knockout and knockin mice models that allow for the modulation of activity of p38, NEMO, JNK, AKT, ERK1/2, and p53, among others, in podocytes as well as established various knock-in and knock-out models for imaging and genetic analyses using CRISPR/Cas genome engineering technologies.

Potential future therapeutic implications
An overarching aim of this study is to identify the underlying molecular mechanisms of injury that are amenable to potential therapeutic inter-ventions to combat the increasingly prevalent progressive CKD. It is expected that interventions that target the inflammatory and stress signaling process per se will provide a promising new approach to attack a large group of overlapping disorders through an innovative intervention.

Added value through collaborations within the CCRC
This project assimilates well into the framework of the proposed graduate program since it will unravel novel mechanistic insights into podocyte and microvascular dysfunction at the interface of the kidney filtration barrier. Further extension of existing collaborations with the groups of J. Brüning (mouse models, metabolism, posttranslational modifications), M. Pasparakis (mouse models, ER stress, cell death), S. Rosenkranz (signal transduction, kinase networking), and B. Schumacher (stress signaling) will enable us to identify unifying pathogenic principles of stress-induced vasculopathies using the latest mouse models and state-of-the-art technology. In addition, utilization of technology provided by the core facilities will be beneficial to this project: RNAScope and Nanostring (Histopathology; A. Quaas / R. Büttner), mass spectrometry based proteomics (C. Frese / M. Krüger), and sequencing (Functional Genomics; P. Nürnberg). Of note, all our mouse models are also available to all other groups within this consortium. Finally, we predict that the conserved mechanisms of vascular damage through attack on pericyte-like cells of the vascular system may also be applicable to other organs.

Professor Thomas Benzing

Project description

Glomerular disease represents a major cause of chronic kidney disease affecting more than 5% of all human beings world-wide. These disorders share common features such as proteinuria and the loss of renal function due to progressive damage of the glomerular microcirculation. Inflammation conveys the development of glomerular injury and is a major cause of  progressive kidney disease. We have inhibited NF-κB signaling in podocytes, the pericyte-like visceral epithelial cells of the glomerular capillaries, by specific ablation of the NF-κB essential modulator (NEMO, IKKγ). Podocyte-restricted NF-kB inhibition was highly protective in experimental models of glomerular injury. Mice with podocyte-restricted NEMO ablation recovered much faster after damage, showed rapid remission of proteinuria and displayed robust restoration of the glomerular microcirculation suggesting that proinflammatory signaling in podocytes, the pericytes of the glomerular microcirculation, is essential for progressive injury. Thus, the aim of this project is to further define the mechanisms how inflammatory signaling in podocytes contributes to progressive damage of the glomerular microcirculation. We will specifically study the underlying mechanisms of injury that are amenable to develop therapeutic interventions to develop novel treatments of progressive glomerular disease.

 

Prof. Benzing Profile

Thomas Benzing is Professor of Medicine and Chairman of the Department II of Internal Medicine, University of Cologne, and a world-leading specialist for kidney diseases, molecular nephrology and genetics. He received his medical doctor at the University of Freiburg, Germany, and his clinical training and research expertise at the University of Freiburg, the Institute of Cardiovascular Physiology in Frankfurt and at Harvard Medical School in Boston (MA). After serving as Professor of Medicine, Vice Director of the Renal Division and Board Member of the Center for Systems Biology at the University of Freiburg, Benzing moved to Cologne where he is Professor and Chairman at the Department of Medicine. In addition, he is also one of the coordinators of the Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated ­Diseases (CECAD), Director of the Center for Molecular Medicine, University of Cologne as well as coordinator of the Systems Biology of Ageing Cologne (Sybacol) initiative.

Benzing has authored numerous high-ranking publications contributing seminal discoveries to the field of molecular nephrology and is also on the editorial board of several leading international journals including Science Signaling, Journal of the American Society of Nephrology, etc. Further, Benzing‘s work has also been acknowledged by his being awarded with numerous prizes including the Franz-Volhard prize of the German Society of Nephrology, the Buding research award of the German Society of Hypertension, the Young Investigator Award of the American Society of Nephrology and the Ernst-Jung Award for Medicine. Finally, he is an Honorary Fellow of the American Society of Nephrology and elected member of the Ludwig-Heilmeyer Society and the German National Academy of Sciences Leopoldina.

 

Research interests

There is an ever-increasing proportion of the ageing population affected by renal disease and hypertension. Although ”normal ageing“ does not necessarily cause dramatic changes in the reduction of kidney‘s filtration rate, a strongly increased incidence of hypertension and a high susceptibility to acute kidney failure are very common findings. For example, more than 30% of the population over the age of 65 present with chronic renal disease (CKD), hypertension or susceptibility to acute renal injury. Importantly, it is now clear that renal damage and CKD are major independent risk factors for cardiovascular morbidity and mortality including stroke, myocardial infarction and heart failure. Thus, age-related kidney disease is among the most important non-neoplastic lesions that affect overall morbidity and mortality in the ageing population. To date, the main causes of age-related renal pathologies are not well understood; however, genetic as well as environmental factors are known to play a role. The Benzing group studies molecular mechanisms of progressive kidney ageing and dysfunction of the renal ultrafiltration units using mouse and Drosophila melanogaster as model organisms. Moreover, the lab also addresses signalling networks in renal carcinogenesis, longevity pathways in C. elegans that are regulated through kidney-expressed oncogenes, and the dynamics of carcinogenesis and ageing. Finally, it also studies the effects of new therapies using molecular systems biology.

 

Previous scientific achievements

The team of Professor Benzing studies the molecular ­basis of kidney diseases focussing on disorders of the kidney filtration barrier, cilia-related diseases and age-related ­pathologies. They have pioneered the concept of signalling at the slit diaphragm, a specialized cell junction at the kidney filtration barrier. Together with collaborating investigators all over the world they deciphered the function of this protein complex and its role in controlling the biology of podocytes, essential structures at the kidney filtration barrier. Moreover, the team has investigated signalling through cilia, sensory organelles that play a role in controlling animal survival and longevity. Seminal studies of the lab have led to the discovery of novel genes involved in controlling the pathogenesis ciliopathies and a variety of age-related kidney disorders.