Mechanismen des "biased signalling" durch Gerinnungsproteasen: Charakterisierung einer neuen Interaktion von Protease-aktivierten Rezeptoren und Integrinen bei glomerulären Erkrankungen.
Zusammenfassung der Projektergebnisse
Despite wide range of cellular expression and extensive investigation of the activation mechanisms exerted by plethora of proteases, the spatial and temporal regulation of class A GPCRs-protease activated receptors (PARs) and its pathophysiological relevance remain unknown. Here we show in specialized renal epithelial cells podocytes that, integrin αvβ3 controls protease-dependent spatial and temporal regulation of PAR signaling. Coagulation protease activated protein C (aPC), which has pleotropic cytoprotective effects through PARs in various rodent disease models, binds to integrin αvβ3 and temporally regulates PAR signaling. However, abolishing aPC-αvβ3 interaction or knockdown of αvβ3 integrin alters spatial and temporal kinetics of PARs receptor resulting in sustained-cell disruptive signaling. Likewise, in vivo, in a mouse model of diabetic nephropathy (dNP), overexpression of integrin binding deficient aPC-mutant or deletion of integrin β3 specifically in podocytes abrogates cytoprotective effects of aPC. More importantly, in vivo antagonizing integrin αvβ3 signaling or inhibition of sustained PAR signaling protects against dNP. Corroborating our results in murine dNP, analysis of human dNP in Nephroseq (a human renal disease database) revealed increased expression and activation of αvβ3 associated with altered PAR receptor expression specifically within the podocytes. These results identify integrin-αvβ3 as a rheostat that control temporal and spatial regulation of PAR signaling in mouse and human disease.
Projektbezogene Publikationen (Auswahl)
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Negative interactions and feedback regulations are required for transient cellular response. Sci Rep. 2014 Jan 16;4:3718
Mobashir M, Thati Madhusudhan, Isermann B, Beyer T, Schraven B
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Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination. J Am Soc of Nephrol 2015 Nov;26(11):2789-99
Wei Dong, Hongjie Wang, Khurrum Shahzad, Fabian Bock, Satish Ranjan, Juliane Wolter, Shrey Kohli, Juliane Hoffmann, Vishnu Mukund Dhople, Jonathan A. Lindquist, Charles T. Esmon, Thati Madhusudhan, Peter Mertens, Dirk Schlüter, Berend Isermann
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Defective podocyte insulin signaling through p85-XBP1 promotes ATF6 dependent maladaptive ER-stress response in diabetic nephropathy. Nature Communications 2015 Mar 10; 6:6496
Thati Madhusudhan, Hongjie Wang, Wei Dong, Sanchita Ghosh, Berend Isermann et al.
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Nlrp3-inflammasome activation in non-myeloid-derivedcells aggravates diabetic nephropathy. Kidney Int. 2015 Jan;87(1):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, Söderkvist P, Groß O, Schwenger V, Pahernik S, Nawroth PP, Gröne HJ, Thati Madhusudhan, Isermann B
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Caspase-1, but not caspase-3, promotes diabetic nephropathy. J Am Soc Nephrol. 2016 Feb 1
Shahzad K, Bock F, Al-Dabet MM, Gadi I, Kohli S, Nazir S, Ghosh S, Ranjan S, Wang H, Thati Madhusudhan, Nawroth PP, Isermann B
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Emerging role of coagulation protease signaling in kidney disease. Nature Reviews Nephrology 2016 Feb; 12(2):94-109
Thati Madhusudhan, Bryce A. Kerlin, Berend Isermann
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Farnesoid X Receptor Agonism Protects against Diabetic Tubulopathy: Potential Add-On Therapy for Diabetic Nephropathy. J Am Soc Nephrol July 2017
Andi Marquardt, Moh′d Mohanad Al-Dabet, Gosh S, Kohli S, Manoharan J, Ihsan Gadi, Fabian Bock, Sumra Nazir, Hongjie Wang, Peter P. Nawroth, Thati Madhusudhan, Khurrum Shahzad, Berend Isermann
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Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease aPC with insulin like function. Blood July 2017
Thati Madhusudhan, Wang H, Ghosh S, Wei D, Wolfram Ruf, Isermann B et. al.
