Characterization of the mechanisms of biased coagulation protease signalling: Novel cross talk between protease activated receptor and integrin signalling in glomerular disease.
Final Report Abstract
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.
Publications
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Negative interactions and feedback regulations are required for transient cellular response. Sci Rep. 2014 Jan 16;4:3718
Mobashir, Mohammad; Madhusudhan, Thati; Isermann, Berend; Beyer, Tilo & Schraven, Burkhart
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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
Dong, Wei; Wang, Hongjie; Shahzad, Khurrum; Bock, Fabian; Al-Dabet, Moh'd Mohanad; Ranjan, Satish; Wolter, Juliane; Kohli, Shrey; Hoffmann, Juliane; Dhople, Vishnu Mukund; Zhu, Cheng; Lindquist, Jonathan A.; Esmon, Charles T.; Gröne, Elisabeth; Gröne, Herman-Josef; Madhusudhan, Thati; Mertens, Peter R.; Schlüter, Dirk & Isermann, Berend
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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
Madhusudhan, Thati; Wang, Hongjie; Dong, Wei; Ghosh, Sanchita; Bock, Fabian; Thangapandi, Veera Raghavan; Ranjan, Satish; Wolter, Juliane; Kohli, Shrey; Shahzad, Khurrum; Heidel, Florian; Krueger, Martin; Schwenger, Vedat; Moeller, Marcus J.; Kalinski, Thomas; Reiser, Jochen; Chavakis, Triantafyllos & Isermann, Berend
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Emerging role of coagulation protease signaling in kidney disease. Nature Reviews Nephrology 2016 Feb; 12(2):94-109
Madhusudhan, Thati; Kerlin, Bryce A. & Isermann, Berend
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Nlrp3-inflammasome activation in non-myeloid-derivedcells aggravates diabetic nephropathy. Kidney Int. 2015 Jan;87(1):74-84
Shahzad, Khurrum; Bock, Fabian; Dong, Wei; Wang, Hongjie; Kopf, Stefan; Kohli, Shrey; Al-Dabet, Moh'd Mohanad; Ranjan, Satish; Wolter, Juliane; Wacker, Christian; Biemann, Ronald; Stoyanov, Stoyan; Reymann, Klaus; Söderkvist, Peter; Groß, Olaf; Schwenger, Vedat; Pahernik, Sascha; Nawroth, Peter P.; Gröne, Herman-Josef; ... & Isermann, Berend
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Caspase-1, but not caspase-3, promotes diabetic nephropathy. J Am Soc Nephrol. 2016 Feb 1
Shahzad, Khurrum; Bock, Fabian; Al-Dabet, Moh’d Mohanad; Gadi, Ihsan; Kohli, Shrey; Nazir, Sumra; Ghosh, Sanchita; Ranjan, Satish; Wang, Hongjie; Madhusudhan, Thati; Nawroth, Peter P. & Isermann, Berend
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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
Marquardt, Andi; Al-Dabet, Moh’d Mohanad; Ghosh, Sanchita; Kohli, Shrey; Manoharan, Jayakumar; ElWakiel, Ahmed; Gadi, Ihsan; Bock, Fabian; Nazir, Sumra; Wang, Hongjie; Lindquist, Jonathan A.; Nawroth, Peter Paul; Madhusudhan, Thati; Mertens, Peter R.; Shahzad, Khurrum & Isermann, Berend
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Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease aPC with insulin like function. Blood July 2017
Madhusudhan, Thati; Wang, Hongjie; Ghosh, Sanchita; Dong, Wei; Kumar, Varun; Al-Dabet, Moh'd Mohanad; Manoharan, Jayakumar; Nazir, Sumra; Elwakiel, Ahmed; Bock, Fabian; Kohli, Shrey; Marquardt, Andi; Sögüt, Ibrahim; Shahzad, Khurrum; Müller, Andreas J.; Esmon, Charles T.; Nawroth, Peter P.; Reiser, Jochen; Chavakis, Triantafyllos; ... & Isermann, Berend
