Histones from Dying Renal Cells Aggravate Kidney Injury via ... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Allam, Ramanjaneyulu*,†; Scherbaum, Christina Rebecca*; Darisipudi, Murthy Narayana*; Mulay, Shrikant R.*; Hägele, Holger*; Lichtnekert, Julia*; Hagemann, Jan Henrik*; Rupanagudi, Khader Valli*; Ryu, Mi*; Schwarzenberger, Claudia‡; Hohenstein, Bernd‡; Hugo, Christian‡; Uhl, Bernd§; Reichel, Christoph A.§; Krombach, Fritz§; Monestier, Marc‖; Liapis, Helen¶; Moreth, Kristin**; Schaefer, Liliana**; Anders, Hans-Joachim*

*Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany;

†Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;

‡Division of Nephrology, University of Dresden, Dresden, Germany;

§Walter Brendel Centre of Experimental Medicine, University of Munich, Munich, Germany;

‖Temple Autoimmunity Center, Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania;

¶Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri; and

**Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany

R.A., C.R.S., and M.N.D. contributed equally to this work.

Correspondence: Dr. Hans-Joachim Anders, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Pettenkoferstr. 8a, D-80336 Munich, Germany. Email: [email protected]

Received November 15, 2011

Accepted May 2, 2012

Abstract

In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-κB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.