Necroptosis in Acute Kidney Injury

Mini Review

Austin J Nephrol Hypertens. 2016; 3(2): 1059.

Necroptosis in Acute Kidney Injury

Liu W¹* and Xia Y²*

¹School of Medicine, Yunnan University, China

²School of Biomedical Sciences, Chinese University of Hong Kong, China

*Corresponding author: Wenjing Liu, School of Medicine, Yunnan University, Kunming, Yunnan 650091, China

Yin Xia, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China

Received: August 02, 2016; Accepted: September 05, 2016; Published: September 07, 2016


Acute kidney injury (AKI) is a common clinical entity associated with high morbidity and mortality. Tubular epithelial cell death plays a key role in the development of AKI. Although apoptosis has been the focus of the studies on kidney injury and drug discovery for many years, recent studies have identified signaling pathways and regulatory mechanisms for programmed necrosis or necroptosis. It is now clear that receptor-interacting kinase 1 (RIP1), RIP3 and its substrate, the pseudokinase mixed lineage kinase domain-like protein (MLKL) are the core components of necroptosis. Increasing evidence from pharmacological and genetic studies shows that necroptosis plays critical roles in progression of AKI in several mouse models. In this review, we aim to briefly summarize the mechanisms and functions of necroptosis in AKI.

Keywords: Acute kidney injury; Necroptosis; Loss and End-stage kidney disease


Acute kidney injury

Acute kidney injury (AKI) is characterized by rapid declines in kidney functions within one week. AKI affects millions of patients worldwide with high mortality, morbidity and cost. Stages of kidney failure in AKI are defined using either Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) staging criteria or Acute Kidney Injury Network (AKIN) staging criteria. The RIFLE acronym represents the rising severity grades: risk, injury and failure, and the two outcome criteria: loss and end-stage kidney disease. The severity grades from risk to failure are defined based on increasing serum creatinine and decreasing urine output. The two outcome categories, loss and end-stage kidney disease, are defined by the duration of loss of kidney function [1]. However, the AKIN staging system includes the entire spectrum of symptoms, from tiny impairment in kidney function to the need for renal replacement therapy [2].

Using the RIFLE classification, studies from all around the world revealed that 2-7% of the hospitalized patients suffered from AKI, and the incidence is steadily increasing [3]. From the studies of the incidence of AKI in an intensive care unit in Australia from 2000 to 2005, 36.1% of patients suffered from AKI [4]. AKI is associated with an increased mortality in hospitalized patients.

The cause of acute kidney injury is grouped into three classes: prerenal, renal (with direct intrinsic renal damage) and postrenal injury [5]. Prerenal acute kidney injury is caused by diseases in cardiovascular system such as systemic hypotension, severe systolic cardiac failure and volume depletion, which lead to reduction in renal perfusion and glomerular filtration. Intrinsic acute kidney injury is the consequence of destruction of nephron structure, and it results from ischemic or nephrotoxic injury, such as acute progressive glomerulopathies, acute interstitial nephritis and acute tubular necrosis. Postrenal acute kidney injury is attributed to obstruction of the urinary tract, which causes reduced glomerular filtration rate and renal failure.

Approximately one third of the AKI result from direct or indirect nephrotoxicity, and two-thirds result from renal ischemiareperfusion or sepsis [6]. Although AKI has various etiologies, it is frequently associated with ischemic and toxic insults. AKI occurs commonly in the setting of sepsis. The pathophysiology of sepsisassociated AKI is very complex, but it involves the changes as seen in ischemic, toxic or obstructive nephropathy, including inflammatory response, oxidative stress and microvascular dysfunction [7]. In laboratory science, the molecular events of AKI are most commonly studied in rodents with ischemia-reperfusion injury induced by clamping of both renal pedicles. Other models used in laboratories include cisplatin- or folic acid-induced toxic injury and sodium oxalate-induced crystal nephropathy. Accordingly, our knowledge regarding the mechanisms of AKI has been mostly obtained from studies in rats and mice with ischemia/reperfusion-induced AKI.

Tubular epithelial cells play active roles in the development of AKI. In response to various insults, tubular epithelial cells die, leading to tubular atrophy and even kidney failure [8]. Although acute tubular necrosis is a key feature of AKI, previous studies were directed toward apoptosis because apoptosis was considered to be the only genetically programmed and therapeutically targetable form of cell death in AKI while necrosis was thought to be a nonregulated response to overwhelming stress. Apoptosis is a caspase-dependent programmed cell death, and is characterized by cell shrinkage, chromatin condensation, nuclear fragmentation and membrane blebbing [9]. Apoptosis of renal IRI was first described in 1992 [10], and subsequently it was shown that blockade of apoptosis with IGF-1 or the pan caspase inhibitor zVAD-fmk prevented renal function impairment after IR [11]. Therefore, for a long time, strategies targeting the apoptosis pathway were widely explored for AKI treatment. Despite the substantial therapeutic effect in animal models, efficient anti-apoptosis intervention strategies are still absent in clinic.

Studies in the past decade have found that necrosis can be a regulated or programmed process. Receptor-interacting protein kinase (RIP)1 and RIP3-mediated necroptosis [12,13] is the best studied regulated necrosis pathway. Necroptosis is characterized by cytoplasmic granulation and organelle or cellular swelling that together result in cell membrane rupture and release of intracellular contents [14]. Unlike apoptotic cells, which are rapidly phagocytosed by macrophages or neighboring cells, necrotic cell death including necroptosis provokes sterile inflammation by the damage-associated molecular patterns (DAMPs) formulated from the released intracellular contents. Therefore, necroptosis not only participates in the development of organism but also is critically involved in various pathological processes including ischemic injury in brain, heart and kidney [12,15-18], atherosclerosis [19], pancreatitis [20], inflammatory bowel diseases [21] and viral infection [22]. Emerging evidence indicates that AKI involves necroptosis, and that the necroptotic pathway may be used for therapeutic intervention to limit AKI [17,18,23,24].

The pathways of necroptosis

As shown by Figure 1, necroptosis can be activated when cells are treated with TNF family cytokines, including TNFα, Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) [25]. Ligation of TNF to TNF receptor (TNFR)1 causes formation of receptorassociated complex I, which contains TNFR1, TNFR1-associated death domain (TRADD), TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein (cIAP) 1, cIAP2, the linear ubiquitin chain assembly complex (LUBAC) and RIP1. CIAPs and LUBAC promote RIP1 ubiquitination at Lys-11 and Lys-63, and linear ubiquitin linkages. Ubiquitination of RIP1 further recruits additional factors, including transforming growth factor (TGF) β-activated kinase (TAK1), TAK1-binding protein 2 (TAB2) and the inhibitor of the NF-κB kinase (IKK), and ultimately activates the NF-κB pathway [26].

Citation: Liu W and Xia Y. Necroptosis in Acute Kidney Injury. Austin J Nephrol Hypertens. 2016; 3(2): 1059. ISSN : 2381-8964