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
Patients with CKD display massively increased cardiovascular calcifications, which contribute to their higher cardiovascular mortality risk. Matrix Gla protein is an essential vascular calcification inhibitor when carboxylated through vitamin K-dependent mechanisms. We hypothesize that absolute or relative (functional) vitamin K deficiency in CKD patients can be treated to such a degree that we can fully correct this deficiency in order to maximize clinical benefit. This project aims to characterize in detail the dysregulation of vitamin K-dependent mechanisms of vascular calcification in CKD and will thereby reveal novel approaches towards the development of more rational and possibly novel therapeutic ways to halt progress of or even induce regression of cardiovascular calcifications in CKD patients.
Project C-02: The role of post-translational modifications of sortilin receptors in CKD
Recently, we identified the intracellular sorting receptor sortilin as a calcification promotor and the soluble, circulating form as a cardiovascular risk factor in the general population. We demonstrated that circulating sortilin is post-translationally modified in patients with impaired kidney function. The overall hypothesis is that circulating sortilin undergoes directed post-translational modification and thereby functionally promotes cardiovascular calcification. This project aims to characterize in detail the mechanisms and importance of post-translationally modified sortilin in CKD. This may lead to the development of potential therapies targeting post-translational protein modifications and thereby provide opportunities to treat CVD in CKD.
Project C-03: Role of Protein-Mineral Complexes in Mineral Homeostasis
CKD patients develop extensive and progressive vascular calcification that contributes to the high cardiovascular morbidity and mortality. Calciprotein monomers (CPM) stabilize amorphous calcium-phosphate precursors, which, if they grow and crystallize, start a vicious cycle of cell and matrix calcification and inflammation. This project aims to elucidate the atomic structure of CPM, their stability and biological activity. This may lead to the identification of early-stage, modifiable molecular targets to diagnose and stop CVD and CKD-associated cardiovascular inflammation and calcification, before irreversible vicious cycles have started.
Project C-04: Characterization and validation of mediators affecting myocardial infarction and vascular calcification in CKD
We recently contributed towards the elucidation of the vascular calcification process via the detailed functional characterization of two previously identified calcification inhibitors, as well as the identification of two novel calcification mediators from hemofiltrate of CKD patients. This project will now provide deeper insight into the cardiovascular protective effects of the identified mediators in the context of myocardial infarction and vascular calcification. Also, it will study post-translational modifications (PTMs) in CKD and novel strategies to limit PTM-associated pathological changes, stimulating new therapeutic approaches to tackle increased cardiovascular risk in CKD patients.
Project C-05: Dissecting mechanisms of vascular calcification in CKD using single cell genomics
Vascular sclerosis with calcification in media and intima is a major contributor to cardiovascular morbidity and mortality in patients with chronic and end-stage renal disease. We hypothesize that targeting vascular calcification is a key strategy to reduce cardiovascular morbidity and mortality in CKD. Here, using a combination of established cutting edge single cell technologies including single cell RNA-sequencing, measurement of DNA accessibility (ATAC-seq) and spatial gene expression, this project will dissect the complex cellular and molecular mechanisms of vascular calcification. The ultimate goal is to identify novel druggable targets and develop targeted therapeutics for vascular calcification in CKD.
Project C-07: CKD and coagulation: dysregulation of the alternative complement pathway
Patients with CKD display alterations in the coagulation system resulting in an increased thrombotic and bleeding risk, which causes an augmented cardiovascular risk in these patients. We recently demonstrated incorporation of complement C3 into fibrin clots, leading to a prothrombotic clot structure with thinner fibrin fibres and resistance to fibrinolysis. Recent findings raised the hypothesis that not only complement C3 itself but also complement activation may play an important role in prothrombotic clot alterations in CKD. This project will study the hypothesis that a dysregulation of the alternative complement pathway in CKD results in a prothrombotic phenotype and thereby increased cardiovascular risk in CKD patients.
Project C-08: Role of hematopoietic reprogramming in cardiorenal diseases
Inflammation represents a crucial mediator of CKD and CVD alike. Our recent findings underscore the relevance of inflammation in CKD-associated CVD by engaging a specific innate immune pathway, i.e. by NLRP3 inflammasome activation. This project aims to gain novel pathophysiological insights into the effects of CKD and CVD on the hematopoietic compartment and the regulation of hematopoiesis in general. The results obtained should improve the understanding of cardiorenal disease mechanisms and identify novel anti-inflammatory treatment approaches to halt the progression of CKD and the development of its associated cardiovascular complications
Project C-09: Dickkopf-3 (DKK3) as a mediator of cardiorenal injury
Tissue fibrosis represents a hallmark of advanced CKD and CVD leading to final organ failure. Recent experimental work in various CKD models has documented the crucial involvement of the Wnt/β-catenin pathway in the development of tubulointerstitial fibrosis and thus progressive CKD. Dickkopf-3 (DKK3) is a member of the Dickkopf protein family, which is closely involved in the regulation of the Wnt/β-catenin signaling. This project aims to systematically dissect the impact of DKK3 on cardiorenal injury and to assess on whether modulation of DKK3 may provide a specific therapeutic target in the management of CKD and its cardiovascular complications.
Project area C - Circulation
Project area M - Myocardium
Project M-01: PDGFR signaling in CVD in CKD
We have recently defined the role of PDGFR in CKD, particularly in mediating fibrosis and angiogenesis. Our pilot data showed an increased expression of PDGFR-α in uremic cardiomyopathy and vasculopathy. This project aims to analyze our hypothesis, that PDGFR-α signaling mediates CKD-associated CVD, which will stimulate further translational development of PDGFR-based diagnostic and therapeutic approaches also the pathological kidney-heart crosstalk in CKD patients.
Project M-02: Role of renal sympathetic nerve activation in CKD-associated cardiovascular disease and the development of malignant arrhythmias
CKD is associated with atrial pro-arrhythmic remodeling and activation of the sympathetic nervous system, a known trigger for atrial fibrillation. This project aims to deliver deeper insights into the effect of renal sympathetic signaling on the development of malignant arrhythmias in a multifactorial experimental model of cardiovascular comorbidities, as seen in patients with CKD. Furthermore, it will shed light on renal denervation as an interventional tool to prevent cardiac arrhythmia in CVD-associated comorbidities and CKD.
Project M-03: Modulatory effects of SGLT2 inhibition on cardiac metabolism in CKD patients
CKD induces processes of accelerated aging in the heart, termed uremic cardiomyopathy (UC), leading to cellular senescence, degeneration and fibrosis by yet incompletely understood mechanisms. This projects will investigate altered cardiac metabolism in CKD: it aims to decipher the underlying metabolic pathways leading to altered cardiac substrate utilization in CKD and will investigate the cardioprotective mechanisms of SGLT2 inhibition in CKD.
Project M-04: Interplay between calcium signaling and oxidative stress in pathogenic immune cells during CKD and associated CVD
Inflammation is a major factor determining progression of CKD and the development of cardiovascular complications. This project aims to specifically unravel the interplay between Ca2+ signaling and oxidative stress as central regulators of inflammation during CKD and its associated cardiovascular complications. It will provide detailed mechanistic insights into altered ion channel profiles in CKD and their interplay with local generation of reactive oxygen species, leading to altered pro-inflammatory cytokine release and the modulation of immune and cardiac cells contributing to cardiorenal pathology.
Project M-05: Enhanced thrombotic risk and myocardial dysfunction of the infarcted heart in CKD
We recently revealed a maladaptive preconditioning of the heart in CKD towards adverse cardiac remodeling after myocardial infarction. Furthermore, CKD patients display increased thrombotic risk. This project will study alterations of regulatory processes in the heart post-myocardial infarction in CKD. Also, it will examine the effect of CKD on platelet responses in relation to the increased thrombotic risk along with enhanced bleeding risk in patients with CKD. Combined, it will provide novel insights and potential novel therapeutic strategies to target increased cardiovascular risk in CKD patients.
Project M-06: Effects of genetic Raf kinase inhibitor protein (RKIP), RAAS and eNOS modulation on adverse cardiovascular remodeling and senescence in CKD
We recently discovered that 129/Sv mice are highly susceptible to myocardial maladaptive remodeling in CKD. Based on these findings, this project aims to pinpoint the effects of RAAS and eNOS signaling in cardiac remodeling and senescence in CKD and the cell type-specific role of RKIP, with the overall goal to better understand the mechanisms of CKD-induced myocardial fibrosis and identify possible future targets for prevention or therapy.
Project M-07: Immune cell-lipid interaction, a mechanism of CKD-induced vascular complications
CKD patients display a massively increased cardiovascular risk compared to those without CKD, but the underlying mechanisms are not well understood. We observed that in CKD ApoA-I/HDL undergoes post-translational modifications, resulting in dysfunctional proinflammatory HDL, which directly activates intraepithelial lymphocytes (IELs) in mice. IELs were recently identified as important contributors for the development of CVD. By using spectral flow cytometry, single cell RNA sequencing and transgenic mouse models, we aim to prove the hypothesis that the interaction of modified-ApoA- 1/HDL and IELs aggravates CKD-induced vascular complications like atherosclerosis. Targeting IELs might be a novel therapeutical approach for the treatment of patients with CKD and high cardiovascular risk.
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
Within the 1st funding period, this service project has intensively supported the entire consortium in the translation of experimental hypotheses into clinical practice through biobank coordination. This service project will now continue to provide an essential clinical translational hub to all the partners within this consortium to gain deeper insights into the clinical relevance and significance of newly identified mediators and biomarkers in CKD-associated CVD pathology.
Project S-02: Central platform for standardization and development of animal models and histopathological analyses
This central platform provides intensive support to all researchers of SFB/TRR219 in standardized animal models for CKD-CVD, functional in vivo analyses, and reproducible tools for the assessment of cardiac and renal histo-pathology. In this context, this platform has intensively and successfully cooperated with all consortium partners within the first funding period. For the second funding period, the service project aims to continue this intensive support and collaboration of the entire consortium on animal models and histo-pathological analyses and further refine existing and develop novel models and analysis tools.
Project S-03: Mass spectrometry to identify, quantify and localize novel regulators of pathological processes underlying CKD-associated CVD
We have demonstrated that mass spectrometry is a powerful beyond the state-of-the-art technique that, when combined with chromatographic separation and functional assays, enables the identification of novel regulators and underlying mechanisms and regulators of pathological processes. Furthermore, mass spectrometry is an ideal method to study post-translational modifications (PTMs) of proteins and peptides, with a broad spectrum of PTMs identified in the first funding period to be involved in the pathology of CKD-associated CVD. By using a combination of chromatography, mass spectrometry and MALDI imaging, this service project will continue to provide a critical 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: Cardiovascular complications in CKD
Within the first funding period of the SFB/TRR219, we established the integrated Research Training Group (IRTG) "Cardiovascular complications in CKD" intending to provide an interdisciplinary training program to all doctoral researchers (PhDs and MDs) associated with the consortium. Our structured curriculum during the second funding period will build on our well-established structures, with the aim to guide our doctoral students to become the next generation of innovative, independent, and translational cross-disciplinary researchers in the interdependencies of the cardiorenal system and beyond to discover innovative solutions in diagnosis and therapy.
Project area Z – Administrative project
Project Z-01: Central administrative project
The Z project is the administrative project of SFB/TRR219. It serves to organize all the joint tasks within the SFB/TRR219. This includes the distribution of the funding, the coordination and administration, the organization of seminars and meetings of the SFB/TRR219 including travel, and all the logistics including internet activities and public relations.