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

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

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 therapeu-

tic regimens based on manipulating both apoptotic and regulated necrotic pathways.

and clinical implications from the clinician's underground.

**2. Apoptosis in AKI**

**2.1. Signaling pathways of apoptosis**

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

The classic apoptosis can be activated by the intrinsic and extrinsic pathways that both rely on the involvements of caspases [13]. To date, the signaling pathways of apoptosis

which are absolutely distinct from programmed cell death [3].

4 Current Understanding of Apoptosis - Programmed Cell Death

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 process of toxic renal injury [23].

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

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