Shruthi Krishnan

Postdoc              

Initial hypothesis and aims of the project

Based on previously published data and our preliminary data, we hypothesize that CD248 promotes diabetic kidney disease (DKD) by inhibiting the adaptive UPR response, but also by promoting maladaptive signaling. Specifically, we hypothesize that CD248 enhances ATF4 and ATF6α signaling via the UPR, inducing the maladaptive transcription factor CHOP and inflammation by modulating NF-κB signaling. Based on preliminary data and the function of UPR- and mTORC1-signalling in DKD, we also hypothesize that CD248-mediated mTORC1 pathway regulates UPR signaling, thus contributing to renal inflammation and cell death in DKD.

Aims of the project:

1. Identification of the role of CD248 in regulating the maladaptive UPR arms PERK-ATF4-CHOP and ATF6α-CHOP as well as NF-κB activation in diabetic kidney disease.
2. Characterization of the role of CD248 for mTORC1–mediated renal inflammation and the interplay between mTORC1 and maladaptive UPR signaling in diabetic kidney disease.

Shruthi Krishnan

PhD Student

Yanfei Yu

PhD Student

Berend Isermann

Project Leader

Michael Naumann

Project Leader

Diabetic nephropathy (dNP), now the most common cause of chronic renal disease, is characterized by dysfunctional barriers in the glomerular and tubular compartments. A common cell type found in both renal compartments are pericytes, which interact with epithelial (EpiC) and endothelial (EndoC) cells. Maladaptive pericyte activation impairs barrier function and promotes kidney fibrosis, a common final pathway in kidney damage. Targeting pericyte function may allow protection of both renal compartments. However, specific strategies to target pericytes are currently lacking. TEM1 (tumor endothelial marker 1, CD248, or endosialin) is a protein expressed by pericytes in various organs, including the kidney and the stomach. Expression of TEM1 is high during development in tumors and during inflammatory diseases. In a clinical study low TEM1 expression by cancer associated fibroblast correlates with increased survival of gastric cancer patients. However, the mechanisms underlying TEM1-dependent effects remain poorly defined. In cooperative work (Project P7) we analyzed TEM1 regulation and the unfolded protein response (UPR) and established a role of TEM1 in renal pericytes in the context of dNP. We hypothesize that pericyte derived TEM1 co-ordinately regulates barrier function in chronic diseases. Specifically, we define the molecular mechanism and functional consequences of intracellular signaling via TEM1 between pericytes and barrier-defining epithelial cells, and conduct a structure function analyses of TEM1 to identify the molecular structures required for barrier regulation to determine whether modulating TEM1 function allows to rescue epithelial cells and thus barrier function. Two PhD students jointly address questions about the regulation of the UPR in the context of renal cells (Shruthi Krishnan) and H. pylori-infected gastric mucosal cells (Yanfei Yu).

UPR regulation in DKD and H. pylori infection. (A) TEM-1 expressing cells in the kidney (blue; mesangial cells, top, and peritubular pericytes, bottom) interact with endothelial cells (red), podocytes (yellow, top), and tubular cells (yellow, bottom). (B) Schematic diagram of UPR signalling.