Alterations in the circulation as well as in the myocardium crucially contribute to the increased cardiovascular risk in patients with CKD. Our consortium SFB/TRR219 will investigate the mechanisms that underlie increased cardiovascular risk in the context of CKD, with a main focus on calcification, inflammation, oxidative stress and fibrosis, in addition to alterations in thrombosis and neurohumoral activity.
Pathological mechanisms underlying increased CVD risk in patients with CKD
-Our joint efforts to examine these mechanisms in the circulation (C projects) as well as in the myocardium (M projects) underlines the interaction between the kidney, circulation and myocardium. Furthermore, the SFB/TRR219 consortium integrates three service projects (S projects) as central platforms. First, a centralized hub for analysing and integrating all clinical studies and experimental data using bioinformatics and statistical methods will facilitate the implementation of experimental concepts into clinical medicine (project S-01). A second platform will provide standardized and harmonized animal models and histopathological analyses of cardiovascular and renal pathology to the consortium to facilitate comparability and synergy between all projects (project S-02). A third project combines chromatography, mass spectrometry and MALDI imaging to enable all consortium partners to gain deep insights into the pathology of CKD-associated cardiovascular disease (project S-03).
-The Central Administration Project (Z project) is responsible for all core functions and for the coordination within the SFB/TRR219 consortium.
-In addition, the SFB/TRR219 consortium has integrated a PhD graduate school (IRTG project) to guide PhD students to become the next generation of innovative, independent and translational cross-disciplinary researchers exploiting multiple facets of cardiovascular disease in CKD.
Complementary approach of our Transregional Collaborative Research Center to investigate in both the circulation and the myocardium the mechanisms underlying increased cardiovascular risk in CKD patients.
Project C-01: Vitamin K-dependent mechanisms of cardiovascular calcification in CKD
Cardiovascular calcifications contribute to the drastically increased CV mortality of patients with CKD. Lack and/or dysregulation of calcification inhibitors are essential pathomechanisms of CV calcifications. The vascular calcification inhibitor MGP is activated by vitamin K-dependent carboxylation within the vasculature, but is increasingly uncarboxylated in CKD patients. We hypothesize that this functional vitamin K deficiency in CKD plays an essential role in the pathogenesis of CV calcifications and that this system can be modified therapeutically. This project aims to better characterize the dysregulation of vitamin K-dependent mechanisms of vascular calcification in CKD.
Project C-02: The role of the VPS10 domain receptor family in cardiovascular calcification in CKD
Clinical evidence demonstrates that cardiovascular calcium burden significantly predicts cardiovascular events. Particularly, patients with CKD are susceptible to cardiovascular calcification and thus harbor a higher risk for clinical complications. The scientific purpose of this research proposal is to examine the cellular and molecular mechanisms that facilitate the nidus for vascular calcification in CKD. This project will test the hypothesis that Vps10 domain sorting receptors are crucially involved in the development of CVD in patients with CKD by promoting fibro-calcific vascular remodeling.
Project C-03: The pathophysiology of lipidic calcified particles in CKD
The hepatic plasma protein fetuin-A stabilizes colloidal protein-mineral complexes in the form of calciprotein particles (CPPs), and mediates their clearance from the circulation. CKD patients have reduced free serum fetuin-A and an increased CPP-bound fetuin-A, which is associated with cardiovascular mortality. Our preliminary work suggests that CPPs bind to lipoproteins to form lipidic calcified debris, which we hypothesize to cause inflammation and calcification in CKD. This project will study the biochemistry, metabolism and biological activity of lipidic calcified particles in CKD.
Project C-04: Isolation, identification and characterization of mediators affecting vascular calcification in CKD
Vascular calcification significantly contributes to cardiovascular morbidity and mortality, especially in patients with CKD. In a calcification screening assay of bovine adrenal gland extracts, we identified “calcification blocking factor” (CBF) and “vasoconstriction-inhibiting factor” (VIF) as two novel peptides that strongly reduce vascular calcification in vitro and show decreased or increased plasma levels, respectively, in CKD patients compared with healthy controls. Thus, we hypothesize that decreased CBF levels in CKD patients contribute to their increased vascular calcification rate, whereas increased VIF levels in CKD patients represent a protective factor in vascular calcification processes with a yet entirely unknown mode of action for VIF. This project aims to confirm this hypothesis as well as to isolate, identify and characterize further mediators affecting vascular calcification in CKD.
Project C-05: Dissecting mechanisms of adventitial progenitor recruitment driving vascular calcification in CKD
Vascular calcification contributes centrally to the dramatically increased cardiovascular mortality in CKD. We have recently identified an adventitial Gli1+ progenitor population in the vascular wall driving vascular calcification in CKD. We propose that Gli proteins are critical cell-cycle regulators in Gli1+ cells and drive their expansion in vascular injury and disease while pharmacologic inhibition of Hedgehog-Gli might be a therapeutic strategy in vascular calcification. Furthermore, we propose that platelets and platelet-derived proteins such as Cxcl4 and sortilin are critical activators of Gli1+ cell recruitment and transdifferentiation. This project aims to investigate this hypothesis and dissect the mechanisms of Gli1+ adventitial progenitor recruitment driving vascular calcification in CKD.
Project C-07: CKD and coagulation: the impact of complement activation
A compact fibrin clot structure is associated with more severe CVD. Recently, we identified a denser clot structure to independently predict mortality in CKD patients receiving hemodialysis therapy. This might be at least partially due to our observation that fibrinogen from hemodialysis patients, but not from healthy controls, was glycosylated and guanidinylated. Further, subjects with CKD exhibit increased complement C3 activation, and complement activation products are detectable in clots. This project will provide mechanistic insight into the effect of post-translational modifications and complement (activation) products on clot properties in CKD.
Project C-08: Role of microRNA and post-translational modifications of HDL in CKD-associated vascular disease
CKD represents one of the strongest risk factors for the occurrence of vascular events. Apart from traditional risk factors, endothelial dysfunction, vascular calcification, impaired regeneration of vascular lesions, and a pro-inflammatory microenvironment are known to promote CVD in patients with impaired kidney function. We previously showed that uremia transforms high-density lipoprotein (HDL) and low-density lipoprotein (LDL) into noxious pro-inflammatory particles. This project will examine how post-translational modifications of HDL-associated proteins as well as HDL-associated miRNA in CKD modulate the effects of HDL on vascular regeneration, vascular calcification and inflammatory cell activation.
Project C-09: Role of interleukin-1α in CKD-associated cardiovascular complications
We recently identified that lipoproteins from CKD patients enhance IL-1α release from monocytes. It is suggested that IL-1α represents a key alarmin, thereby initiating systemic inflammation. We hypothesize that IL-1α plays an important role in CKD-associated systemic inflammation contributing to CKD-related cardiovascular complications. This project aims to examine how alterations of lipoproteins in CKD modulate IL-1α production/secretion in a translational study design. Also, we will investigate the role of IL-1α in crucial processes underlying the development of CKD-associated CVD.
Project area C - Circulation
Project area M - Myocardium
Project M-01: PDGF - a mediator of CVD in CKD
Platelet-derived growth factor (PDGF) exerts pro-fibrotic, proliferative and anti-apoptotic effects on PDGF receptor (PDGFR)-bearing mesenchymal cells, i.e. fibroblasts, pericytes and vascular smooth muscle cells, thereby driving cardiac fibrosis and arteriosclerosis. Our pilot data suggest an upregulation of PDGF in uremic cardiomyopathy. We hypothesize, that PDGF also mediates CVD in CKD, which would render it a highly attractive pharmacological target in CKD associated with CVD. This projects aims to tackle this hypothesis and investigate PDGF as a potential mediator of CVD in CKD.
Project M-02: Impact of neurohumoral activation in CKD on the development of an arrhythmogenic substrate in the atrium
The prevalence of atrial fibrillation (AF) in patients with CKD is ~2-3 times higher compared to that in the general population. In CKD, neurohumoral activation, particularly the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS), may underlie atrial structural and electrophysiological changes and the development of AF. Additionally, conditions in CKD may be associated with an imbalance of the receptor for advanced glycation end-products (RAGE) and its soluble neutralizer (sRAGE), further contributing to AF maintenance by activation of maladaptive remodeling processes in the atrium. This project aims to gain understanding of the link between renal sympathetic afferent nerve signaling and AF in CKD by applying renal denervation in the 5/6 nephrectomy rat model.
Project M-03: Metabolic and mitochondrial dysregulation in uremic cardiomyopathy
Uremic cardiomyopathy (UC) is a major complication of CKD. Previous studies have linked UC with mitochondrial dysfunction, oxidative stress, and changes in substrate metabolism with altered glucose utilization due to insulin resistance in CKD. Therefore, CKD may lead to the development of UC through effects on insulin and AMPK signaling resulting in impaired energy supply and mitochondrial dysfunction. Further, we hypothesize that GLP-1 and/or its metabolite GLP-1 (9-37) -based therapies may also exhibit cardioprotective properties in UC through their positive effects on mitochondrial function and cardiac metabolism. This project will examine the role of cardiac mitochondrial dysfunction, energy metabolism, as well as insulin and AMPK signaling in the development of UC.
Project M-04: The role of mitochondrial oxidative stress for cardiac remodeling in CKD
CKD and heart failure are common comorbidities. The mechanisms that underlie this close interaction, however, are incompletely resolved, but inflammation, neuroendocrine activation, as well as oxidative stress have been put forward. This project will investigate the hypothesis that mitochondrial ROS production contributes to maladaptive cardiac remodeling and dysfunction in CKD, and that mitochondrial therapies protects from CKD-induced heart failure.
Project M-05: Inflammatory mediators linking CKD to adverse cardiac remodeling after MI
Patients with CKD experience poor outcomes after acute myocardial infarction (MI). We hypothesize that CKD increases the vulnerability of the heart and negatively affects its remodeling after MI through chemokines/cytokines and uremic toxins as crucial CKD-associated inflammatory mediators that adversely affect cardiomyocytes and fibroblasts. This project aims to characterize the detrimental effects of CKD on cardiac remodeling after MI in CKD in detail.
Project M-06: Effects of CKD on myocardial remodeling and fibrosis
Myocardial fibrosis is the hallmark of highly prevalent cardiac disease phenotypes, which are both increased and aggravated in patients with CKD. We hypothesize that profibrotic signaling is an important complication of CKD, and the identification of the underlying mechanisms may trigger the development of specific therapeutic options for prevention or treatment of cardiac fibrosis and remodeling in CKD, which are still missing. Therefore, this project aims to examine the effects of renal damage on myocardial remodeling and fibrosis in detail and elucidate the yet unknown underlying cellular and molecular mechanisms.
Project area S – Service projects
Project S-01: Translational integration and evaluation of experimental concepts by evaluation of cohorts from clinical studies, international registries and center-based cohorts
Building on our successful clinical study center established during the DFG-funded Clinical Research Group KFO196, this service project will enable and support the clinical translation of experimental hypotheses within this consortium. We will manage a translational database in clinical studies in the context of CKD and CVD in CKD based on already available biobanks, as well as apply bioinformatics and statistical modeling to perform correlation studies planned by the consortium partners. This approach will visualize the clinical relevance of experimental concepts, with the ultimate goal to facilitate translation of concepts into the clinic.
Project S-02: Central platform for standardization and development of animal models and histopathological analyses
This service project will provide all researchers of this consortium with animal models of CKD-CVD and histopathological analyses of cardiovascular and renal pathology. Specifically, we will provide standardized and reproducible CKD-CVD animal models, as well as develop novel animal models that will allow further detailed studies of CVD associated with CKD. Further, we will offer standardized histopathological and ultrastructural analyses, as well as develop stainings and morphometric protocols specifically tailored to the needs of the researchers within the consortium.
Project S-03: Mass spectrometry to identify novel regulators of pathological processes underlying CKD-associated CVD
Patients with CKD have an increased risk of CVD, but the underlying mechanisms are not completely understood. We have demonstrated in our previous work that mass spectrometry is a beyond the state-of-the-art technique that, when combined with chromatographic separation and functional assays, enables the identification of novel regulators of pathological processes. By using a combination of chromatography, mass spectrometry and MALDI imaging, this service project will provide a core proteomic facility to the partners within this consortium to gain deeper insights into the pathology of CKD-associated CVD.
Project area IRTG – Integrated Research Training Group
Project IRTG: Integrated Research Training Group
The Integrated Research Training Group (IRTG) “Cardiovascular complications in CKD” will create an interdisciplinary training program to guide the PhD students within the TRR219 to become the next generation of innovative, independent and translational cross-disciplinary researchers exploiting multiple facets of CVD in CKD. The structured curriculum involves (a) individual research projects (subprojects of the TRR219) and training courses; (b) secondments between the TRR219 partners; (c) a hands-on training module; as well as (d) specialized modules for the development of basic scientific competences and cross-disciplinary skills
Project area Z – Administrative project
Project Z-01: Central Administration Project
The Central Administration Project is primarily focused on administrative, scientific and integrative tasks and will be responsible for running the daily affairs of the Transregional Collaborative Research Center TRR219. The subproject is responsible for all core functions and for the coordination within the Transregional Collaborative Research Center. Thus, this project will ensure an efficient workflow and timely realization of the objectives of the respective subprojects.