**1. Introduction**

The balance between cell survival and cell death laid the foundation for any individual organisms. Cell death, especially molecularly regulated cell death, has been extensively investigated for decades in life science and medicine. Historically, cell death was roughly classified as different types: apoptosis and necrosis [1]. The term "apoptosis" derives from ancient Greek and refers to the developmentally programmed and molecularly controlled cell death, with featured morphologic changes including cell shrinkage, nuclear and cytoplasmic condensation,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

DNA fragmentation, and the formation of apoptosomes [2]. Necrosis, differently, was well recognized as an accidental cell death, with unique characteristics consisting of cellular swelling, breakdown of plasma membrane integrity, and release of intracellular contents, all of which are absolutely distinct from programmed cell death [3].

have been well delineated and for the integrity of the present review, we only emphasize on the basic and major signal events of classic apoptosis. The mitochondria are the crucial converging site for the intrinsic and extrinsic signaling [14]. And specifically, mitochondrial outer membrane permeabilization (MOMP) serves as the key to initiate the final steps of apoptosis. MOMP results in the release of pro-apoptotic components of mitochondria, including cytochrome c, AIF, etc., and thereby the activation of subsequent apoptotic executive mediators [15]. MOMP can be regulated by BCL2 family proteins consisting of pro- and anti-apoptotic factors [10]. Bax and Bak are the main members of BCL2 family and serve as promoters for MOMP; Bcl-2 and Bcl-XL, in contrast, play just the opposite role. Notably, the balance between the two parts determines the fates of cells. In the intrinsic pathway, several cellular stresses including DNA damage, intracellular calcium overload and growth factor ablation can directly induce MOMP. In response to the release of cytochrome c, apoptosome consisting of caspase 9, Apaf-1 and cytochrome c is formed in plasma, which initiates the execution of apoptosis. In the extrinsic pathway, ligation of death receptors results in the formation of DISC, which recruits adapter proteins subsequently leading to combination of caspase-8/FLIP heterodimer and caspase-8 homodimer. The homodimer then cleaves effector proteins caspases-3, -6 and -7 and thereby finishes the execution of apoptosis [16]. It is worthy to note that the extrinsic pathway is able to amplify the apoptotic signals by initiating the intrinsic pathway through caspase-8-independent

From Apoptosis to Regulated Necrosis: An Evolving Understanding of Acute Kidney Injury

http://dx.doi.org/10.5772/intechopen.74816

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As early as 1992, Schumer et al. have demonstrated the first evidence for the existence of apoptosis in AKI with morphologic, biochemical, and molecular detection methods [17]. Thereafter, studies about the role of apoptosis AKI and relevant potential therapeutic modalities have been under intensive investigations. Overwhelming reports exhibited that apoptosis is functionally relevant to various kinds of AKI, of which ischemia–reperfusion injury (IRI) is the most well documented [18, 19]. Besides, sepsis is another common cause of AKI, especially in the intensive care units. Studies demonstrated that apoptosis serves as an important foundation for the pathogenesis of sepsis-related AKI [20–22]. In addition to IRI and septic renal injury, toxic kidney injury is also a common clinical condition contributing to a high rate of morbidity and mortality. Cisplatin, for instance, is a widely-used chemotherapy drug with relatively high nephrotoxicity. As supposed, apoptosis plays a vital role in the pathologic

In the context of AKI, apoptotic cells are detected in different types of renal tissues within both cortical and medullary regions. The most common sites are the renal tubules, especially the proximal tubules [10]. Besides, AKI can also cause apoptosis in other renal cells, for exam-

Collectively, these studies proved the widely occurrence and definitely great functional contributions of renal apoptosis during AKI. The apoptosis was supposed as the most prominent cell death in AKI for nearly two decades, until increasing evidence shows regulated necrosis

ple the vascular endothelial cells which in turn deteriorate kidney damages [24, 25].

is to great extent responsible for the pathogenesis of AKI as well.

activation of tBid, which can cause MOMP [14].

**2.2. The contribution of apoptosis to AKI**

process of toxic renal injury [23].

Caspase-dependent apoptosis is the first identified programmed form of cell death and was regarded as the only form of regulated cell death for a very long time. However, this restricted view has been challenged with the findings of new types of regulated cell death. Exciting breakthroughs in recent years have identified a group of novel forms of cell death, with morphologic features of necrosis but molecularly controlled, termed regulated necrosis [4]. According to the recommendations of Nomenclature Committee on Cell Death (NCCD), the types of regulated necrosis are composed of necroptosis, mitochondrial permeability transition (MPT)-mediated regulated necrosis (MPT-RN), parthanatos, ferroptosis, and pyroptosis [5]. Nowadays, it is well documented that regulated necrosis broadly participates in various biological processes including organism development, immune defenses and various pathophysiological processes [4, 6]. An accumulating body of evidence has demonstrated that regulated necrosis contributes to the pathogenesis of numerous diseases and damages in different organs or tissues [4, 6, 7].

Acute kidney injury (AKI), with a heavy health burden globally, still remains a severe condition in daily clinical routines to date [8]. It is estimated that every year approximately 13.3 million people are diagnosed with AKI and AKI contributes to about 1.7 million deaths around the world per year [9]. In the past, apoptosis was supposed as the predominant form of cell demise that is responsible for renal dysfunction during AKI [10]. Much study in recent years have indicated that programmed form of cell death, no matter apoptosis or regulated necrosis, plays an important role in keeping kidney tissue homeostasis as well as contributing to the pathogenesis of AKI [11, 12]. Different methods targeting the apoptotic molecular signals have been widely explored for AKI treatment. In spite of the solid protective effects of these treatments observed in animal models, the experimental anti-apoptosis intervention strategies cannot still be translated into medical practice, which might be, at least partially, due to our ignorance of regulated necrosis in the process of AKI. An improved understanding of the pathogenesis of AKI under the view of regulated cell death might provide potential therapeutic regimens based on manipulating both apoptotic and regulated necrotic pathways.

Therefore, in this chapter, we summarized the molecular pathways of both apoptosis and regulated necrosis, and reviewed the potential roles and corresponding mechanisms of various cell deaths in AKI based on recent advances. We further discussed the therapeutic potentials and clinical implications from the clinician's underground.
