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      Autophagy in proximal tubules protects against acute kidney injury

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          Abstract

          Autophagy is induced in renal tubular cells during acute kidney injury, however, whether this is protective or injurious remains controversial. We address this question by pharmacologic and genetic blockade of autophagy using mouse models of cisplatin- and ischemia-reperfusion induced acute kidney injury. Chloroquine, a pharmacological inhibitor of autophagy, blocked autophagic flux and enhanced acute kidney injury in both models. Rapamycin, however, activated autophagy and protected against cisplatin-induced acute kidney injury. We also established a renal proximal tubule-specific autophagy-related gene 7 knockout mouse model shown to be defective in both basal and cisplatin induced autophagy in kidneys. Compared with wild-type littermates, these knockout mice were markedly more sensitive to cisplatin-induced acute kidney injury as indicated by renal functional loss, tissue damage, and apoptosis. Mechanistically, these knockout mice had heightened activation of p53 and c-Jun N terminal kinase, signaling pathways contributing to cisplatin acute kidney injury. Proximal tubular cells isolated from the knockout mice were more sensitive to cisplatin-induced apoptosis than cells from wild-type mice. In addition, the knockout mice were more sensitive to renal ischemia-reperfusion injury than their wild-type littermates. Thus, our results establish a renoprotective role of tubular cell autophagy in acute kidney injury where it may interfere with cell killing mechanisms.

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          Most cited references25

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          The role of Atg proteins in autophagosome formation.

          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
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            Pathophysiology of ischemic acute kidney injury.

            Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event leading to unacceptably high morbidity and mortality, development of chronic kidney disease (CKD), and transition from pre-existing CKD to end-stage renal disease. Data indicate a close interaction between the many cell types involved in the pathophysiology of ischemic AKI, which has critical implications for the treatment of this condition. Inflammation seems to be the common factor that links the various cell types involved in this process. In this Review, we describe the interactions between these cells and their response to injury following ischemia. We relate these events to patients who are at high risk of AKI, and highlight the characteristics that might predispose these patients to injury. We also discuss how therapy targeting specific cell types can minimize the initial and subsequent injury following ischemia, thereby limiting the extent of acute changes and, hopefully, long-term structural and functional alterations to the kidney.
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              Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.

              The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.
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                Author and article information

                Journal
                0323470
                5428
                Kidney Int
                Kidney Int.
                Kidney international
                0085-2538
                1523-1755
                20 June 2012
                01 August 2012
                December 2012
                01 June 2013
                : 82
                : 12
                : 1271-1283
                Affiliations
                [1 ]Department of Cellular Biology and Anatomy, Georgia Health Sciences University and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
                [3 ]Department of Pharmacology and Toxicology, Georgia Health Sciences University and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
                [2 ]Tokyo Metropolitan Institute of Medical Science, Setagayaku, Tokyo 156 8501, Japan
                Author notes
                [* ] Corresponding author: Zheng Dong, Ph.D. Department of Cellular Biology and Anatomy Georgia Health Sciences University and Charlie Norwood VA Medical Center 1459 Laney Walker Blvd. Augusta, GA 30912 Phone: (706) 721-2825 Fax: (706) 721-6120 zdong@ 123456georgiahealth.edu
                Article
                NIHMS385446
                10.1038/ki.2012.261
                3491167
                22854643
                72aacf8c-9fbe-46ad-b625-94842aa6a2d0
                History
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK087843 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK058831 || DK
                Categories
                Article

                Nephrology
                autophagy,atg7,cisplatin,ischemia-reperfusion,acute kidney injury
                Nephrology
                autophagy, atg7, cisplatin, ischemia-reperfusion, acute kidney injury

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