Mitochondria-targeted therapies for acute kidney injury

Tábara, Luis Carlos; Poveda, Jonay; Martín-Cleary, Catalina; Selgas, Rafael; Ortíz, Alberto; Sanchez-Niño, María Dolores

doi:10.1017/erm.2014.14

Cited by 80 publications

(89 citation statements)

References 149 publications

(227 reference statements)

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“…38,39 Molecules generated within injured cells have also been recently identified as potential targets to abrogate inflammation. 40 For example, the cysteine proteases (calpains and caspases) play a role in hypoxia-induced injury in proximal tubular cells, and mitochondrial mediators are gaining interest as potential antiinflammatory targets in several cell types. Inhibitors of mitochondrial permeability transition pore opening, quinone analogs, superoxide dismutase mimetics, SzetoSchiller peptides, and mitochondrial division inhibitors have already shown promise in diverse models of AKI, and Figure 2.…”

Section: Basic Concepts Of Inflammationmentioning

confidence: 99%

“…40 Finally, microRNAs generated in injured renal tubular cells are also gaining interest as potential targets. 41,42 In summary, a large and rapidly expanding array of inflammatory cell types and molecular mediators has been implicated in the pathogenesis of AKI, and data from rodent models have clearly shown that deletion, blockade, or enhancement of many of these can improve experimental outcomes.…”

Section: Basic Concepts Of Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

Inflammation in AKI

Rabb

Griffin

McKay

et al. 2016

Journal of the American Society of Nephrology

472

343

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Inflammation is a complex biologic response that is essential for eliminating microbial pathogens and repairing tissue after injury. AKI associates with intrarenal and systemic inflammation; thus, improved understanding of the cellular and molecular mechanisms underlying the inflammatory response has high potential for identifying effective therapies to prevent or ameliorate AKI. In the past decade, much knowledge has been generated about the fundamental mechanisms of inflammation. Experimental work in small animal models has revealed many details of the inflammatory response that occurs within the kidney after typical causes of AKI, including insights into the molecular signals released by dying cells, the role of pattern recognition receptors, the diverse subtypes of resident and recruited immune cells, and the phased transition from destructive to reparative inflammation. Although this expansion of the basic knowledge base has increased the number of mechanistically relevant targets of intervention, progress in developing therapies that improve AKI outcomes by modulation of inflammation remains slow. In this article, we summarize the most important recent developments in understanding the inflammatory mechanisms of AKI, highlight key limitations of the commonly used animal models and clinical trial designs that may prevent successful clinical application, and suggest priority approaches for research toward clinical translation in this area.

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Section: Basic Concepts Of Inflammationmentioning

confidence: 99%

Section: Basic Concepts Of Inflammationmentioning

confidence: 99%

Inflammation in AKI

Rabb

Griffin

McKay

et al. 2016

Journal of the American Society of Nephrology

472

343

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“…Renal IRI often occurs in partial nephrectomy, renal transplantation and various urological vascular surgeries that may transiently reduce renal blood flow [7]. Renal IRI is a risk for acute renal failure and delayed graft function clinically [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Propofol Prevents Renal Ischemia-Reperfusion Injury via Inhibiting the Oxidative Stress Pathways

Zhong

Lei

et al. 2015

Cell Physiol Biochem

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Background/Aims: Renal ischemia/reperfusion injury (IRI) is a risk for acute renal failure and delayed graft function in renal transplantation and cardiac surgery. The purpose of this study is to determine whether propofol could attenuate renal IRI and explore related mechanism. Methods: Male rat right kidney was removed, left kidney was subjected to IRI. Propofol was intravenously injected into rats before ischemia. The kidney morphology and renal function were analyzed. The expression of Bax, Bcl-2, caspase-3, cl-caspase-3, GRP78, CHOP and caspase-12 were detected by Western blot analysis. Results: IR rats with propofol pretreatment had better renal function and less tubular apoptosis than untreated IR rats. Propofol pretreated IR rats had lower Bax/Bcl-2 ratio and less cleaved caspase-3. The protein expression levels of GRP78, CHOP and caspase-12 decreased significantly in propofol pretreated IR rats. In vitro cell model showed that propofol significantly increased the viability of NRK-52E cells that were subjected to hypoxia/reoxygenation (H/R) in a dose-dependent manner. The effect of propofol on the expression regulation of Bax, Bcl-2, caspase-3, GRP78, CHOP was consistent in both in vitro and in vivo models. Conclusion: Experimental results suggest that propofol prevents renal IRI via inhibiting oxidative stress.

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“…In the following sections, consideration will be given to the respective merits of each of these approaches. As this article is focused on strategies currently in vogue, older targets will not be discussed, such as inhibitors of the mitochondrial permeability transition pore, which have been covered in depth elsewhere [11].…”

Section: Mitochondrial-targeted Therapiesmentioning

confidence: 99%

Mitochondria as therapeutic targets in acute kidney injury

Hall

Schuh

2016

Current Opinion in Nephrology and Hypertension

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PURPOSE OF REVIEW: Mitochondria are complex intracellular organelles with a variety of important functions. The kidney tubule is densely packed with mitochondria, and mitochondrial dysfunction is thought to be central to the pathogenesis of acute kidney injury (AKI). Mitochondria therefore represent potential targets for novel therapeutic interventions in AKI. RECENT FINDINGS: Several mitochondrial targeted approaches have shown promise in recent preclinical studies of AKI, including measures to: reduce oxidative stress within mitochondria; prevent mitochondrial fission and activation of cell death pathways; enhance recycling of damaged mitochondria via autophagy and mitophagy; and accelerate mitochondrial biogenesis postinsult. SUMMARY: Recent studies show that it is now eminently feasible to pharmacologically manipulate various key aspects of mitochondrial biology in the kidney, and this has much potential for the future treatment of AKI. However, significant hurdles will have to be overcome in the translational pathway for these strategies to successfully migrate to the clinic. Purpose of review Mitochondria are complex intracellular organelles with a variety of important functions. The kidney tubule is densely packed with mitochondria, and mitochondrial dysfunction is thought to be central to the pathogenesis of acute kidney injury (AKI). Mitochondria therefore represent potential targets for novel therapeutic interventions in AKI. Recent findingsSeveral mitochondrial targeted approaches have shown promise in recent preclinical studies of AKI, including measures to: reduce oxidative stress within mitochondria; prevent mitochondrial fission and activation of cell death pathways; enhance recycling of damaged mitochondria via autophagy and mitophagy; and accelerate mitochondrial biogenesis postinsult. SummaryRecent studies show that it is now eminently feasible to pharmacologically manipulate various key aspects of mitochondrial biology in the kidney, and this has much potential for the future treatment of AKI. However, significant hurdles will have to be overcome in the translational pathway for these strategies to successfully migrate to the clinic.

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Mitochondria-targeted therapies for acute kidney injury

Cited by 80 publications

References 149 publications

Inflammation in AKI

Inflammation in AKI

Propofol Prevents Renal Ischemia-Reperfusion Injury via Inhibiting the Oxidative Stress Pathways

Mitochondria as therapeutic targets in acute kidney injury

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