Regulated Cell Death in AKI

BRIEF REVIEW www.jasn.org Regulated Cell Death in AKI † ‡ Andreas Linkermann,* Guochun Chen, Guie Dong, Ulrich Kunzendorf,* Stefan Krautwald,* †‡ and Zheng Dong *Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany; †Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; and ‡Department of Cellular Biology and Anatomy, Charlie Norwood Veterans Affairs Medical Center and Medical College of Georgia at Georgia Regents University, Augusta, Georgia ABSTRACT AKI is pathologically characterized by sublethal and lethal damage of renal tubules. various forms of cell death are noticeable: Under these conditions, renal tubular cell death may occur by regulated necrosis necrosis and apoptosis. This review sum- (RN) or apoptosis. In the last two decades, tubular apoptosis has been shown in marizes the evidence for the various forms preclinical models and some clinical samples from patients with AKI. Mechanistically, of regulated cell death in AKI, delineates apoptotic cell death in AKI may result from well described extrinsic and intrinsic their underlying mechanisms with an em- pathways as well as ER stress. Central converging nodes of these pathways are phasis on the new insights, and puts forth mitochondria, which become fragmented and sensitized to membrane permeabilization the perspectives of targeting cell death for in response to cellular stress, resulting in the release of cell death–inducing factors. the prevention and therapy of kidney injury. Whereas apoptosis is known to be regulated, tubular necrosis was thought to occur by accident until recent work unveiled several RN subroutines, most prominently receptor- interacting protein kinase–dependent necroptosis and RN induced by mitochondrial APOPTOSIS—THE CLASSIC VIEW permeability transition. Additionally, other cell death pathways, like pyroptosis and OF REGULATED CELL DEATH IN ferroptosis, may also be of pathophysiologic relevance in AKI. Combination therapy THE KIDNEY targeting multiple cell-death pathways may, therefore, provide maximal therapeutic benefits. Evidence for Apoptosis in AKI In 1992, Schumer et al.10 showed DNA J Am Soc Nephrol 25: 2689–2701, 2014. doi: 10.1681/ASN.2014030262 cleavage and nuclear condensation during renal IR injury, showing the first evidence of apoptosis in AKI. To date, the fi AKI is a multifactorial and multiphasic dialysis and 30%–70% developing compli- initial observation has been con rmed renal disease characterized by a rapid cations, including CKD and ESRD. The an- and extensively expanded. By morphol- fi decline of renal function, resulting in the nual cost of AKI in the United States is ogy, apoptotic cells are identi ed after accumulation of metabolic waste and estimated to exceed $10 billion.3,4 renal IR by electron microscopy and var- 10–12 toxins and consequent complications Pathologically, AKI is characterized by ious nuclear staining methods. Bio- and failure of other organs. Clinically, renal tubular damage, inflammation, and chemically, renal IR leads to the activation the causes of AKI mainly include sepsis, vascular dysfunction. Injury and death of ischemia-reperfusion (IR) injury, and var- tubular cells are especially recognized as the Published online ahead of print. Publication date ious endogenous as well as exogenous precipitating factors in AKI, and as an ex- available at www.jasn.org. nephrotoxins. It is estimated that over 2 tension, tubular repair and regeneration are Correspondence: Dr. Zheng Dong, Department of million peopledieofAKIeachyeararound considered major events in kidney recovery Nephrology, The Second Xiangya Hospital, Central the world,1 and the prevalence of AKI has from AKI.5–8 Although sublethal injury is South University, Changsha, Hunan, China; and De- partment of Cellular Biology and Anatomy, Medical 1,2 been increasing rapidly. AKI is also reversible, the death of tubular cells is ac- college of Georgia at Georgia Regents University and known for its association with unacceptably companied by the inevitable loss of the Charlie Norwood VA Medical Center, Augusta, GA high rates of mortality. For example, in in- function of the affected cells, and notably, 30912, or Dr. Andreas Linkermann, Clinic for Ne- phrology and Hypertension, Christian-Albrechts- tensive care units, AKI is associated with a it is also frequently the source of damage- University, Kiel, Germany. Email: [email protected] mortality rate of 50%–80%. Notably, even if associated molecular patterns (DAMPs), or [email protected] the patients survived, the post-AKI progno- the stimulating and amplifying factors of Copyright © 2014 by the American Society of sis is dismal, with 7.5% requiring long-term inflammation in tissue damage.9 In AKI, Nephrology J Am Soc Nephrol 25: 2689–2701, 2014 ISSN : 1046-6673/2512-2689 2689 BRIEF REVIEW www.jasn.org of caspases and endonucleases.13,14 In ad- involvement of apoptosis in cisplatin- All aforementioned apoptotic path- dition, regulation of apoptotic genes, in- induced renal injury. In human kidneys ways have been implicated in AKI. The cluding caspases and Bcl-2 family proteins, of sepsis-associated AKI, tubular cell ap- extrinsic pathway of apoptosis mediated has been shown.13–16 optosisisdetectedbyTUNELandacti- by TNF-a and Fas may contribute to tu- vated caspase 3 staining.25 Of note, in bular cell loss in ischemic and septic 43–45 a TUNEL staining and the evalua- some of the previous studies, apoptosis AKI. Consistently, TNF- receptor tion of in vivo cell death. TUNEL has was detected in kidney tissues by a single knockout mice are resistant to cisplatin method, such as TUNEL assay, which AKI, further supporting the involvement been widely used within the last two fi a– decades to evaluate cell death in tis- maybequestionableforitsspeci city of the TNF- mediated extrinsic path- 46 sues. Indeed, most dead cells stain of apoptosis (Box). way in the pathogenesis of AKI. In is- positive for TUNEL, because double- In addition, although tubular apo- chemic and cisplatin nephrotoxic AKI, strand breaks are found in most ptosis has often been reported in various ER stress activation has been documen- models of AKI, the upstream signaling ted, but definitive evidence for the in- programmed cell death. Obviously, – TUNEL positivity is found in apoptotic pathways leading to apoptosis in these volvement in ER stress related apoptosis 47,48 cells, but in contrast to the widespread models can be very different. For example, has yet to be shown. In contrast, the belief, TUNEL positivity is not limited distinct pathogenic mechanisms may be role played by the intrinsic pathway of to apoptosis, because the cells of reg- responsible for apoptosis in ischemic and apoptosis in AKI has been shown con- 26,27 ulated necrosis are TUNEL-positive cisplatin nephrotoxic AKI. vincingly. In 1998, evidence of the acti- as well.173 Therefore, detection of ap- In AKI, apoptotic cells are shown in vation of the intrinsic pathway in AKI optosis requires additional staining both cortical and medullary regions. In was shown by using the experimental (e.g., cleaved caspase 3 [also referred to renal tubules, apoptosis occurs in prox- model of hypoxic incubation of renal tu- 49 as activated caspase 3]) either from tissue imal tubules, distal tubules, and tubular bular cells. In this model, cytochrome ’ 10,12,28–36 lysates in Western blot assays or im- cells of the Henle sloop. Nu- c is released from mitochondria followed mhunohistochemically. The difference merous renoprotective agents seem to by caspase activation and tubular cell between TUNEL staining and positivity ameliorate AKI, at least in part, by apoptosis. Importantly, the activation diminishing tubular apoptosis. For ex- of Bax and Bak, two proapoptotic Bcl-2 for cleaved caspase 3 might even be used fi to quantify the amount of regulated ne- ample, minocycline, a tetracycline de- family proteins, was later con rmed to crosis in tissues,173 butitcannotfurther rivative, blocks apoptosis during renal be key to the mitochondrial leakage or 49–51 specify the precise pathway of regulated IR, which is accompanied by the ame- MOMP. In animals, MOMP associ- necrosis.174 To further distinguish nec- lioration of ischemic renal injury and ated by cytochrome c release was shown 28,37 roptosis from apoptosis, one emerging renal failure. Remarkably, deletion during ischemia and cisplatin nephro- fi 33,37,52 marker for the direct detection of nec- of apoptotic genes speci cally from toxic AKI. The critical roles of proximal tubules results in marked de- Bax and Bak in AKI have been shown roptosis is an mAb that detects phos- – phorylated MLKL.114 This antibody, creases in apoptosis and protection recently using global and proximal tubule fi 39 however, only detects human phos- from both ischemic and nephrotoxic speci cgeneknockoutmodels. Notably, 38,39 phorylated MLKL. AKI. Together, these studies show in humans, mitochondrial damage by Bax an important role of tubular cell apo- and Bak seems to be a key to apoptotic cell ptosis in AKI. death in kidneys injured by ischemia.53,54 Apoptosis is also well recognized in Upregulation of Bcl-2 either pharmacolog- AKI induced by various nephrotoxins. Main Pathways of Apoptosis in AKI ically or by gene transfection consistently For example, cisplatin is a widely used Apoptosis can be initiated through sev- blocks Bax and Bak activation, resulting in cancer therapy drug with a major side eral pathways (Figure 1). In the intrinsic the preservation of mitochondrial integrity effect of nephrotoxicity, which limits it pathway, cell stress directly leads to mito- and cell viability and further supporting a therapeutic efficacy.17,18 Depending on chondrial outer membrane permeabiliza- critical role of the intrinsic pathway of ap- the dosage, cisplatin induces both necro- tion (MOMP), resulting in the release of optosis in tubular injury in AKI.28,49–51 sis and apoptosis in renal tubular cells in apoptogenic factors, including cyto- vitro as well as in vivo in animal models. chrome c, that then bind Apaf-1 to acti- Mitochondria and Bcl-2 Proteins: Apoptosis is shown by cell morphology, vate caspase 9.

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