How Kidney Cell Death Induces Renal Necroinflammation

https://doi.org/10.1016/j.semnephrol.2016.03.004Get rights and content

Summary

The nephrons of the kidney are independent functional units harboring cells of a low turnover during homeostasis. As such, physiological renal cell death is a rather rare event and dead cells are flushed away rapidly with the urinary flow. Renal cell necrosis occurs in acute kidney injuries such as thrombotic microangiopathies, necrotizing glomerulonephritis, or tubular necrosis. All of these are associated with intense intrarenal inflammation, which contributes to further renal cell loss, an autoamplifying process referred to as necroinflammation. But how does renal cell necrosis trigger inflammation? Here, we discuss the role of danger-associated molecular patterns (DAMPs), mitochondrial (mito)-DAMPs, and alarmins, as well as their respective pattern recognition receptors. The capacity of DAMPs and alarmins to trigger cytokine and chemokine release initiates the recruitment of leukocytes into the kidney that further amplify necroinflammation. Infiltrating neutrophils often undergo neutrophil extracellular trap formation associated with neutrophil death or necroptosis, which implies a release of histones, which act not only as DAMPs but also elicit direct cytotoxic effects on renal cells, namely endothelial cells. Proinflammatory macrophages and eventually cytotoxic T cells further drive kidney cell death and inflammation. Dissecting the molecular mechanisms of necroinflammation may help to identify the best therapeutic targets to limit nephron loss in kidney injury.

Section snippets

Evolutional Origins of Inflammation

Any multicellular organism has to maintain the integrity of its tissues. Because multicellular organisms frequently face traumatic injuries, suitable danger response programs need to immediately control the potential fatal threats of fluid (blood) loss, pathogen entry, and tissue instability.18 Plants and animals control these three fundamental dangers by clotting, inflammation, and wound healing, respectively,19 whereas wound healing implies re-epithelialization and scarring.20 Evolution

Renal Cell Necrosis as a Source of Intracellular DAMPs

Genetically controlled forms of necrosis are referred to as regulated necrosis (RN), that is, necroptosis is a receptor-interacting serine/threonine-protein kinase (RIPK)3- and MLKL-mediated form of necrosis.98 Renal cell necroptosis contributes to ATN in several models of kidney injuries.99, 100, 101, 102 Necroptosis involves the release of the alarmin IL-33, which induces inflammation.98, 103 In addition, cyclophilin D–mediated mitochondrial permeability transition-related RN also was

Kidney Diseases with Renal Cell Necrosis

Necrotic lesions inside the kidney usually are driven by a primary vascular necrosis (eg, in crescentic glomerulonephritis or thrombotic microangiopathies). In addition, ischemic tubular necrosis has an important component of peritubular vascular necrosis. We discuss the evidence for necrotic cell death driving inflammation in these disease entities.

Summary

Renal cell loss is rarely a consequence of apoptosis but rather of regulated necrosis, or simply flushing of detached living cells. During AKI, regulated necrosis seems most prevalent, for example, during necrotizing glomerulonephritis, acute tubular necrosis, or thrombotic microangiopathies. Immune cell necrosis (ie, NETosis or pyroptosis), is a likely component of these disorders. Necrosis involves rupture of the plasma membrane, which implies the release of DAMPs and alarmins that ligate

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    Financial support: Supported by the Deutsche Forschungsgemeinschaft (MU 3906/1-1, AN372/11-2, 14-3, 16-1, 20-1, and 23-1 to S.R.M. and H.-J.A.).

    Conflicts of interest statement: none.

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