This grant examines the role of the complement system in the development of ischemic acute renal failure. Our published work demonstrates that complement activation contributes to renal injury after ischemia/reperfusion (I/R), and that activation occurs primarily through the alternative pathway. The alternative pathway has emerged, in recent years, as a critical mediator of injury in a number of different diseases. This system is effective at rapidly eliminating invasive pathogens, but insufficient control of the activating enzymes permits inflammatory injury of host cells. The primary hypothesis of this grant is that hypoxia alters the surface expression of complement inhibitory proteins by proximal tubular epithelial cells. This changes the cells from a complement inhibitory to a complement activating phenotype. Once activated, the alternative pathway triggers generation of pro-inflammatory signals, including C3a, C5a, macrophage inflammatory protein-2 (MIP-2) and keratinocyte derived chemokine (KC). To test this hypothesis we will use in vivo and in vitro models to determine whether the loss of surface inhibition is sufficient to cause spontaneous alternative pathway activation, and the mechanisms by which this surface inhibition is lost after I/R (SA1). Factor H is a potent alternative pathway inhibitor that circulates in high concentrations but fails to prevent alternative pathway mediated injury in certain diseases. We will also examine whether a novel complement inhibitor that targets factor H to the site of complement activation prevents pathological complement activation after renal I/R, and the factors that modulate protection of this surface by endogenous factor H (SA2). Finally, we will examine the mechanisms by which alternative pathway activation in the tubulointerstitium triggers a widespread inflammatory response (SA3). Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. A number of complement inhibitors have become available, including a specific inhibitor of the alternative pathway that has been developed by our laboratory and a targeted inhibitor of the alternative pathway that was developed by one of our collaborators. The proposed studies should help delineate the benefits and limitations of complement inhibition as a therapy for ischemic acute renal failure, as well as expand our understanding of complement activation as a mediator of inflammation after renal tubular injury.
Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. Studies have demonstrated that the complement system is activated within the kidney after ischemia. The proposed experiments examine the complex interactions between the complement system and the kidney. These studies will identify therapies that effectively inhibit the complement system and determine whether these agents will ameliorate ischemic acute renal failure.
|Tomlinson, Stephen; Thurman, Joshua M (2018) Tissue-targeted complement therapeutics. Mol Immunol 102:120-128|
|Goetz, Lindsey; Laskowski, Jennifer; Renner, Brandon et al. (2018) Complement factor H protects mice from ischemic acute kidney injury but is not critical for controlling complement activation by glomerular IgM. Eur J Immunol 48:791-802|
|Luo, Wentian; Olaru, Florina; Miner, Jeffrey H et al. (2018) Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy. Front Immunol 9:1433|
|Klawitter, Jelena; Pennington, Alexander; Klawitter, Jost et al. (2017) Mitochondrial cyclophilin D ablation is associated with the activation of Akt/p70S6K pathway in the mouse kidney. Sci Rep 7:10540|
|Rubtsova, Kira; Rubtsov, Anatoly V; Thurman, Joshua M et al. (2017) B cells expressing the transcription factor T-bet drive lupus-like autoimmunity. J Clin Invest 127:1392-1404|
|Casiraghi, F; Azzollini, N; Todeschini, M et al. (2017) Complement Alternative Pathway Deficiency in Recipients Protects Kidney Allograft From Ischemia/Reperfusion Injury and Alloreactive T Cell Response. Am J Transplant 17:2312-2325|
|Thurman, Joshua M; Frazer-Abel, Ashley; Holers, V Michael (2017) The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases. Arthritis Rheumatol 69:2102-2113|
|Thurman, Joshua M (2017) Getting over our Immune-Complex - C5a receptor blockade is the answer. Cell Mol Immunol 14:319-320|
|Li, Dan; Zou, Lin; Feng, Yan et al. (2016) Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium Transporter Expression During Polymicrobial Sepsis. Crit Care Med 44:e289-99|
|Thurman, Joshua M; Nester, Carla M (2016) All Things Complement. Clin J Am Soc Nephrol 11:1856-1866|
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