Endothelial Cell Function and Vascularization in the Kidney; Molecular mechanisms of Peritoneal Dialysis
Research Group Leader
- Prof. Dr. med. Hermann Haller
- Dr. rer. nat. Nelli Shushakova
- Dr. med. Christoph Schröder
- Uta Hillebrand
- Martin Reinhardt
- Dr. med. Anastasia Paulmann
- Carsten Lindschau
- Julia Kiyan, PhD.
- Sergey Tkachuk, PhD.
- Dr. med. Margret Patecki
- Dr. med. Klaus Stahl
- Ekaterina Chernobrivaia - Graduate Student
- Yannick Becker Graduate Student
- Birgit Habermeier
- Petra Wübbolt-Lehmann
- Michaela Beese
Endothelial cells in the kidney play an important role in the maintenance of blood flow and homeostasis of the organ, and, when dysfunctional, in the pathogenesis of acute (TMA) and chronic (diabetic nephropathy). In particular, we are investigating the role of the endothelial glycocalyx and have described a new molecule, heparanase-2 hpa-2 which is endothelium-protective and can prevent inflammation. We are now studying the structure and mechanism of action of hpa-2 on the endothelium in the microcirculation (organ-on-a-chip), in zebrafish and in mice. We have also recently begun to use a new aging model (African Turquoise Killifish ATK) and are characterizing the aging process of the endothelium in the kidney and other organs. Our hypothesis is that impaired signal transduction of VEGF is responsible for aging and that targeted genetic manipulation can arrest these aging and dedifferentiation processes.
Our second research project deals with the vascularization of renal tissue. The goal is to vascularize organoids and to produce functional kidney tissue from human stem cells. We use zebrafish embryos with genetic markers for renal cells, macrophages and endothelium and LSM microscopy to identify the cellular and molecular mechanisms of vasculogenesis. In parallel, we are studying new vessel formation in human renal organoids. We have discovered that human macrophages strongly influence vascularization and endothelial differentiation and are attempting to identify the factor(s) responsible for angiogenesis from macrophages using scRNA eq and siRNA. The results from the zebrafish experiments and organoids will be translated into a three-dimensional organ-on-a chip model of the vascularized kidney.
Our third area of research is disease models in the mouse. This area is performed in close collaboration with Fa Phenos on the MHH campus. Members of the group (Nelli Shushakowa, Rong Song) are partly employed by Phenos. We have established mouse models for diabetic nephropathy, AKI, chronic renal failure, sepsis, and myocardial infarction and peritoneal dialysis. The latter model is used for studies of the molecular mechanisms of peritoneal fibrosis. In recent years, we have used co-models to identify the PKC isoform alpha PKC-a as a central signal transduction in this process and we are trying to identify the cells responsible for the pathogenesis of peritoneal fibrosis using scRNAseq and to target therapy and prevention of peritoneal fibrosis by using nanoparticles.
Kiyan Y, Tkachuk S, Kurselis K, Shushakova N, Stahl K, Dawodu D, Kiyan R, Chichkov B, Haller H. Heparanase-2 protects from LPS-mediated endothelial injury by inhibiting TLR4 signalling. Sci Rep. 2019 Sep 19;9(1):13591.
Njau F, Shushakova N, Schenk H, Wulfmeyer VC, Bollin R, Menne J, Haller H.Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice.PLoS One. 2020 Jan 14;15(1):e0218494. doi: 10.1371/journal.pone.0218494. eCollection 2020.
Wang L, Balzer MS, Rong S, Menne J, von Vietinghoff S, Dong L, Gueler F, Jang MS,Xu G, Timrott K, Tkachuk S, Hiss M, Haller H, Shushakova N. Protein kinase C α inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate: Kidney Int. 2016 Jun;89(6):1253-67
Current third-party funding