Project Details
Projekt
Pathomechanisms and modulation of impaired angiogenesis in chronic kidney disease (CKD)
Subject Area
Nephrology
Pathology
Pathology
Term
from 2015 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 280564417
Patients with chronic kidney disease (CKD) suffer disproportionately from cardiovascular complications and cardiac death. The pathogenesis is not well understood, and existing strategies to prevent cardiovascular complications have often failed in CKD patients. Based on our previous work, we propose that an impaired capacity to form new capillary vessels in CKD contributes to the burden of cardiovascular disease. Capillary angiogenesis is an indispensable adaptive process to cope with processes such as macrovascular stenosis/occlusion or heart hypertrophy by restoring the perfusion of the affected organs. The overall aim of our proposal is to better understand the pathophysiology of impaired angiogenesis in CKD, and to develop therapeutic approaches to improve capillary formation in CKD. Using a well-established rat model of CKD (subtotal nephrectomy) and previously employed readout systems to assess myocardial capillary density, ischemia-induced capillary angiogenesis in skeletal muscle as well as myocardial infarct size, we propose the following specific aims:First, we will use an inhibitor of prolyl hydroxylase (ICA) to stabilize hypoxia-inducible factors (HIF) in order to improve capillary formation. In preliminary experiments, we have already demonstrated that (a) activation of HIF targets by ischemia is diminished in CKD, and that (b) a non-pharmacological approach (0.1% CO gas) and a pharmacological approach using ICA both applied before ischemia to stabilize HIF greatly improve capillary formation in the ischemic hindlimb of CKD rats. We will now develop this approach as a pharmacological tool in a therapeutic protocol for application after the induction of ischemia. Further, we will assess whether ICA treatment improves myocardial capillary supply and limits myocardial infarct size in CKD rats.Second, we will test the functional role of 2 candidate molecular targets (CCL7 and Metallothionein-1a) for impaired angiogenesis in CKD which were derived from an Affymetrix microarray gene expression screen in ischemic versus non-ischemic limbs from CKD versus control rats, obtained 24 hours after induction of ischemia. Both candidates have known angiogenic properties; their temporal and spatial expression pattern will be investigated. Furthermore, in vitro experiments will be performed to investigate the function of the prolylhydroxylase inhibitor, CCL7 and metallothionein-1a for capillary formation. Proliferation-, apoptosis- and different cell migration assays will be used to elucidate if the potential pro-angiogenic effects of our molecular targets are due to direct actions on endothelial cells (as opposed to indirect effects via e.g. infiltrating mononuclear cells). Subsequently, we will elucidate the signal transduction pathwaysmediating the observed pro-angiogenic effects.From our proposed experiments, we expect novel insight in the pathogenesis of impaired angiogenesis in CKD, and a perspective toward new therapeutic approaches.
DFG Programme
Research Grants
Co-Investigator
Professor Dr. Christoph Daniel
