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

• Final Report Year: 2021

Final Report Abstract

In summary, we were able to demonstrate for the first time: We were able to demonstrate that inflammasome activation precedes glomerular damage and podocytes specific inflammasome genetic inactivation contributes to diabetic nephropathy. Mechanistically mitochondrial ROS and redox regulator p66Shc promotes glomerular inflammasome activation and nephropathy in diabetic mice. Since diabetic nephropathy remains a major therapeutic challenge in diabetic patients, these data could be of translational relevance. We showed that diabetic nephropathy can be therapeutic targeted by IL-R1 antagonist (Anakinra) and mitochondrial anti-oxidant (MitoTEMPO). Furthermore, we also showed that stabilization of endogenous antioxidant Nrf2 by minocycline protects against NLRP3-inflammasome induced diabetic nephropathy. We were able to discover a new anti-inflammatory effect in the context of ischemia reperfusion damage. We showed that cytoprotective coagulation protease activated protein C is an endogenous negative regulator of inflammasome activation after ischemia-reperfusion damage and thus reduces the consequences of myocardial and renal ischemia. Importantly, a biased agonist of PAR-1 (parmodulin-2) mimics inflammasome suppression and cytoprotection after ischemia reperfusion injury. Since ischemia-reperfusion damage continues to be a major clinical challenge, this finding is also relevant.

Publications

• Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination. J Am Soc Nephrol. 2015;26:2789-99
  Dong W, Wang H, Shahzad K, Bock F, Al-Dabet MM, Ranjan S, Wolter J, Kohli S, Hoffmann J, Dhople VM, Zhu C, Lindquist JA, Esmon CT, Grone E, Grone HJ, Madhusudhan T, Mertens PR, Schluter D and Isermann B
  
• Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 2015;87:74-84
  Shahzad K, Bock F, Dong W, Wang H, Kopf S, Kohli S, Al-Dabet MM, Ranjan S, Wolter J, Wacker C, Biemann R, Stoyanov S, Reymann K, Soderkvist P, Gross O, Schwenger V, Pahernik S, Nawroth PP, Grone HJ, Madhusudhan T and Isermann B
  
• Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy. J Am Soc Nephrol. 2016;27:2270-5
  Shahzad K, Bock F, Al-Dabet MM, Gadi I, Kohli S, Nazir S, Ghosh S, Ranjan S, Wang H, Madhusudhan T, Nawroth PP and Isermann B
  
• Stabilization of endogenous Nrf2 by minocycline protects against Nlrp3-inflammasome induced diabetic nephropathy. Sci Rep. 2016;6:34228
  Shahzad K, Bock F, Al-Dabet MM, Gadi I, Nazir S, Wang H, Kohli S, Ranjan S, Mertens PR, Nawroth PP and Isermann B
  
• Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition. Blood. 2017. 10.1182/blood-2017-05-782102
  Nazir S, Gadi I, Al-Dabet MM, Elwakiel A, Kohli S, Ghosh S, Manoharan J, Ranjan S, Bock F, Braun-Dullaeus RC, Esmon CT, Huber TB, Camerer E, Dockendorff C, Griffin JH, Isermann B, Shahzad K
  
• Farnesoid X Receptor Agonism Protects against Diabetic Tubulopathy: Potential Add-On Therapy for Diabetic Nephropathy. J Am Soc Nephrol. 2017;28:3182-3189
  Marquardt A, Al-Dabet MM, Ghosh S, Kohli S, Manoharan J, ElWakiel A, Gadi I, Bock F, Nazir S, Wang H, Lindquist JA, Nawroth PP, Madhusudhan T, Mertens PR, Shahzad K and Isermann B
  
• Thrombin-Induced Podocyte Injury Is Protease-Activated Receptor Dependent. J Am Soc Nephrol. 2017;28:2618-2630
  Sharma R, Waller AP, Agrawal S, Wolfgang KJ, Luu H, Shahzad K, Isermann B, Smoyer WE, Nieman MT and Kerlin BA