Regulation of inflammasome activation in diabetic nephropathy

• Applicant: Dr. Khurrum Shahzad
• Subject Area: Endocrinology, Diabetology, Metabolism ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280167011

Recent data demonstrated that glomerular cells express inflammasome regulators. In addition, non-myeloid derived cells within the kidney contribute to the disease course of diabetic nephropathy. However, unambiguous evidence supporting a pathogenetic role of the inflammasome in glomerular cells is still lacking. Likewise, the functional consequence of the inflammasome in glomerular cells, including the potential role of the non-canonical inflammasome and pyroptosis, are unknown. Furthermore, the mechanisms controlling inflammasome activation in glomerular cells are not known hitherto. Based on preliminary data we hypothesis that inflammasome activation glomerular cells, including in particular podocytes, contributes to glomerulopathy in diabetic nephropathy. We propose that pyroptosis, which is associated with sterile inflammation, is the primordial form of cell death in the context of diabetic nephropathy. Based on preliminary data we postulate that signalling via coagulation proteases, the ER-stress response, mTOR, autophagy, and mitochondrial dysfunction with increased ROS generation controls inflammasome activation in podocytes. Furthermore, based on preliminary data we hypothesize that persistent induction of the inflammasome, potential by epigenetic mechanism, contributes to the metabolic memory, generating a pro-inflammatory micromilieu in the renal glomeruli. To evaluate these hypotheses we will evaluate the following goals: To Goal 1: Defining the cell-autonomous effects of inflammasome activation in podocytes. Within this aim we will use cultured podocytes, in single and mixed cultures, to define the cell-autonomous function of inflammasome regulators in cells of the glomerular filtration barrier. These studies will be combined with in vivo studies using mice with targeted inactivation of inflammasome regulators. To Goal 2: Define the mechanism through which coagulation proteases regulate inflammasome activation in diabetic nephropathy.Within this aim we aim to define the mechanism controlling inflammasome activation in podocytes, focusing on coagulation proteases, their receptors, and potential intracellular signalling via p66Shc or the ER, mTOR, and autophagy. In vitro studies will be combined with in vivo studies. To Goal 3: Characterize the relevance of epigenetic gene induction for persistent inflammasome activation in dNP.Using a combination of in vivo and in vitro approaches we aim to define the relevance and the mechanism of sustained inflammasome activation in the context of diabetic nephropathy.

• DFG Programme: Research Grants