Clinic II for Internal Medicine, University Hospital of Cologne
Age-related kidney diseases are a main cause of morbidity and a major risk factor for stroke, myocardial infarction or dementia. Benzing’s team seeks to unravel the molecular networks in age-related renal pathologies. A major aim is to transfer these findings into new treatment strategies. The lab has pioneered molecular nephrology research of the past decade and provided insights into important human diseases.
Our research: An ever-increasing proportion of the aging population is affected by renal disease and hypertension. Although „normal aging“ does not necessarily cause dramatic changes in kidney function, a strongly increased incidence of hypertension and a high susceptibility to acute kidney failure are very common findings. The causes of age-related renal pathologies are poorly understood but genetic as well as environmental factors clearly play a role. Benzing’s team focuses on the molecular principles of kidney disorders using genetic disorders as a model to unravel the molecular mechanism involved in age-related kidney diseases. They also follow a systems biology approach in studying the underlying signal transduction networks and transfer the findings into the clinics to develop new treatment strategies.
Our successes: In the past decade, Benzing and his team have pioneered the concept of signaling at the slit diaphragm. They showed that this specialized cell junction controls the physiology of the renal filtration barrier and developed tools and techniques to study this regulation. Together with collaborating investigators all over the world they deciphered the function of this signaling complex and its evolutionarily conserved role in controlling intercellular communication and cellular homeostasis in organisms from C. elegans over Drosophila to mice and humans. Moreover, they have investigated signaling through cilia, longevity and cancer. Seminal studies of the lab have led to the discovery of novel genes involved in controlling the pathogenesis of ciliopathies and a variety of age-related kidney disorders.
They recently also identified a novel longevity pathway and showed that deletion of the vhl-1 gene in C. elegans markedly extended lifespan in the nematode. The same pathway reduces susceptibility to various renal insults and slows progression of age-related kidney disease. Benzing’s work has been acknowledged with numerous prizes and awards.
Our goals: A central objective is on the identification of signaling pathways and protein complexes that control stress resistance, homeostasis and intercellular communication in the mammalian kidney. The ultimate goal is to better understand disease-causing molecular mechanisms to develop new treatment options. In a highly interdisciplinary approach they investigate intracellular signalling networks in disease using a systems perspective and the alterations of these networks that occur with age. The tight connection of basic science with an internationally highly recognized clinical expertise provides the unique combination of translating new findings from bench to bedside.
Our methods/techniques: The nephrology lab is headed by Prof. Benzing and Prof. Schermer who also leads his own research team on the molecular pathways of cilia-associated disorders. Their team uses the model organisms C. elegans and Drosophila as well as genetically engineered mice in combination with genetics, molecular biology, proteomics and live imaging as well as genome-wide mRNA and protein expression techniques to study molecular mechanisms of renal pathophysiology. Benzing and his team are involved in numerous international collaborations and also coordinate the systems biology initiative Systems Biology of Ageing Cologne (Sybacol).
Figure 1: The nematode C. elegans is one of the model organisms that greatly facilitates these studies, e.g. due to its simple genetic amenability (unpublished image of a worm expressing GFP under the control of the flcn-1 promoter).
Figure 2: We use this model to identify genes that regulate lifespan and stress resistance through modulation of hypoxia-inducible factor (HIF-1) -signaling (shown here for flcn-1; modied from Gharbi et al. Aging Cell 2013).
Figure 3: GO terms that are enriched in the list of differentially regulated genes found in wild type mouse glomeruli are shown. The lower the p-value of term enrichment the darker the bubble color. Bubble sizes reflect the frequency of a respective GO term in the GO database. We find an enrichment of terms associated with immune response, defense response, proteolysis, endocytosis, and regulation of apoptotic processes in aged glomeruli.
Figure 4: Minimal state networks of WT mice. The graphs show the minimally connected interaction networks of wild type mice. Pink circles indicate all genes that were differentially expressed. Grey circles indicate linker genes. Both networks contain functional modules associated with chemokine receptor signalling, insulin signaling, anti-apoptotic signalling as well as extracellular matrix and complement signalling.
Figure 5: Visualization of single podocytes using mosaic animals. Generation of mosaic expression patterns of Cre recombinase by low-dose tamoxifen induction in R26mTmG x TPod:Cre glomeruli allows for the visualization of secondary processes. Z-projection (average) of ten consecutive confocal slices, covering 0.75 μm (z-step=0.075 μm). Induction of Cre expression was achieved by feeding with a tamoxifen diet for 6 weeks.