Role of the alternative pathway of complement in ischemia/reperfusion and chronic graft injury in a mouse model of kidney allograft

The kidneys play an important role in cardiovascular disease (CVD), where renal co-morbidities accompany CVD in a large proportion of patients thus complicating their treatment regimen. Moreover, the incidence of acute renal injury after cardiac surgery plays an important role in disease progression. Emerging data suggest the importance of understanding the mechanisms of cardio-renal injury and the development of novel therapies that can be safely used with cardiovascular and renal co-existing pathologies. Although the role of G-protein coupled receptors (GPCRs) in CVD has been broadly recognized, their role in renal injury remains poorly understood. We have found, in a chronic mouse model of heart failure, attenuated renal fibrosis and attenuated pathologic RAAS activation by the small molecule GPCR-Gβγ inhibitor “gallein”. To investigate the direct effects of GPCR-Gβγ inhibition on renal injury, we utilized an acute renal ischemia-reperfusion (RIR) mouse model. Gβγ inhibition by gallein pretreatment attenuated the histopathological profile of RIR, including attenuation of tubular hypertrophy, apoptosis, cast formation, and tissue Lipocalin2 expression. This was accompanied by attenuated inflammation, reflected by reduced CCL2 and ICAM1 gene expression and cellular infiltration, in addition to reduced Collagen III gene expression. These preliminary results suggest a promising protective role for Gβγ inhibition in renal injury and remodeling. Future mechanistic investigation of this possible protective effect will provide better understanding of the role of GPCR-Gβγ signaling in cardio-renal injury and remodeling and possible novel therapeutic targets.

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The Role of Platelet Factor 4 in Local and Remote Tissue Damage in a Mouse Model of Mesenteric Ischemia/Reperfusion Injury

PLoS ONE ◽

10.1371/journal.pone.0039934 ◽

2012 ◽

Vol 7 (7) ◽

pp. e39934 ◽

Cited By ~ 23

Author(s):

Peter H. Lapchak ◽

Antonis Ioannou ◽

Poonam Rani ◽

Linda A. Lieberman ◽

Kazuhisa Yoshiya ◽

...

Keyword(s):

Mouse Model ◽

Reperfusion Injury ◽

Tissue Damage ◽

Mesenteric Ischemia ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Platelet Factor 4 ◽

Platelet Factor

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Urine complement activation fragments are increased in patients with kidney injury after cardiac surgery

AJP Renal Physiology ◽

10.1152/ajprenal.00130.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. F650-F657 ◽

Cited By ~ 1

Author(s):

Jennifer Laskowski ◽

Heather Thiessen Philbrook ◽

Chirag R. Parikh ◽

Joshua M. Thurman

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Complement Activation ◽

Alternative Pathway ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Urine Biomarkers ◽

Pathway Activation ◽

Alternative Pathway Of Complement ◽

Subsequent Rise

Experiments in mouse models have shown that the complement cascade is activated within the kidney after ischemia-reperfusion and that complement activation contributes to tubular injury in this setting. Less is known, however, about complement activation in human kidneys after ischemia or whether complement activation in the tubulointerstitium can be detected by measurement of complement fragments in the urine. We hypothesized that urine biomarkers of complement activation would rapidly increase in patients who develop ischemic acute kidney injury, signaling complement activation within the kidney. We confirmed that the alternative pathway of complement is activated in the kidneys of mice after ischemia-reperfusion, and we found that levels of factor B fragments (generated during alternative pathway activation) rapidly increase in the urine. We next performed a case-control study in which we measured complement fragments in human urine samples from patients undergoing cardiac surgery using ELISAs. The level of Ba increased after cardiac surgery and was significantly higher in patients who developed acute kidney injury. The increase in Ba also correlated with magnitude of the subsequent rise in serum creatinine and with the need for hemodialysis during the hospitalization. These findings demonstrate that the alternative pathway of complement is activated in patients who develop acute kidney injury after cardiac surgery and that increases in the level of urine Ba may be a predictive and functional biomarker of severe kidney injury.

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A Novel Targeted Inhibitor of the Alternative Pathway of Complement and Its Therapeutic Application in Ischemia/Reperfusion Injury

The Journal of Immunology ◽

10.4049/jimmunol.181.11.8068 ◽

2008 ◽

Vol 181 (11) ◽

pp. 8068-8076 ◽

Cited By ~ 85

Author(s):

Yuxiang Huang ◽

Fei Qiao ◽

Carl Atkinson ◽

V. Michael Holers ◽

Stephen Tomlinson

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Alternative Pathway ◽

Ischemia Reperfusion ◽

Therapeutic Application ◽

Alternative Pathway Of Complement

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Alternative pathway of complement: recruitment of precursor properdin by the labile C3/C5 convertase and the potentiation of the pathway.

Journal of Experimental Medicine ◽

10.1084/jem.144.4.1076 ◽

1976 ◽

Vol 144 (4) ◽

pp. 1076-1093 ◽

Cited By ~ 133

Author(s):

R G Medicus ◽

O Götze ◽

H J Müller-Eberhard

Keyword(s):

Solid Phase ◽

Alternative Pathway ◽

Critical Role ◽

Membrane Attack Complex ◽

Physiological Role ◽

Enzyme Formation ◽

Degree Of Stability ◽

Alternative Pathway Of Complement

In this study the physiological role of properdin and the differential subunit composition of the solid phase enzymes of the pathway have been explored. Cell-bound C3 and C5 convertase differ in their C3b requirement. Apparently one molecule of C3b is sufficient to allow formation of C3 convertase (C3b,B), whereas two or more are required for generation of C5 convertase (C3bn,B). This conclusion was drawn from results indicating the critical role of the spacial distribution of C3b molecules on the cell surface in enzyme formation. While the C3/C5 convertase is fully capable of acting on C5 and thereby initiating the assembly of the cytolytic membrane attack complex, it is exceedingly labile and vulnerable to destruction by the C3b inactivator. It is the apparent role of properdin to confer a degree of stability upon the labile enzyme and to protect its C3 convertase function against enzymatic destruction. To achieve these effects, precursor properdin (pre-P) is recruited in a binding-activation reaction by the labile C3/C5 convertase. Multiple C3b molecules appear to be needed for the formation of properdin-activating principle. Three modes of regulation have been described, which involve spontaneous dissociation enzymatic degradation by C3b inactivator and disassembly by beta1H. The functional differences of pre-P and activated properdin (P) were delineated, pre-P displaying a weak affinity for C3b and P the capacity of strong interaction, P generating a soluble C3 convertase in serum and pre-P being unable to do so. Because of the profound differences between native pre-P and the laboratory product P, the question was raised as to whether soluble P represents an unphysiological form of the protein. On the basis of this and other studies, the conclusion was reached that in vitro properdin recruitment constitutes the terminal event of the properdin pathway, and that properdin augments the function of C3/C5 convertase without changing its substrate specificity.

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