Autophagy in acute kidney injury Kaushal, Gur P.; Shah, Sudhir V.
Kidney international,
04/2016, Volume:
89, Issue:
4
Journal Article
Peer reviewed
Open access
Autophagy is a conserved multistep pathway that degrades and recycles damaged organelles and macromolecules to maintain intracellular homeostasis. The autophagy pathway is upregulated under stress ...conditions including cell starvation, hypoxia, nutrient and growth-factor deprivation, endoplasmic reticulum stress, and oxidant injury, most of which are involved in the pathogenesis of acute kidney injury (AKI). Recent studies demonstrate that basal autophagy in the kidney is vital for the normal homeostasis of the proximal tubules. Deletion of key autophagy proteins impaired renal function and increased p62 levels and oxidative stress. In models of AKI, autophagy deletion in proximal tubules worsened tubular injury and renal function, highlighting that autophagy is renoprotective in models of AKI. In addition to nonselective sequestration of autophagic cargo, autophagy can facilitate selective degradation of damaged organelles, particularly mitochondrial degradation through the process of mitophagy. Damaged mitochondria accumulate in autophagy-deficient kidneys of mice subjected to ischemia-reperfusion injury, but the precise mechanisms of regulation of mitophagy in AKI are not yet elucidated. Recent progress in identifying the interplay of autophagy, apoptosis, and regulated necrosis has revived interest in examining shared pathways/molecules in this crosstalk during the pathogenesis of AKI. Autophagy and its associated pathways pose potentially unique targets for therapeutic interventions in AKI.
In real-time quantum feedback protocols, the record of a continuous measurement is used to stabilize a desired quantum state. Recent years have seen successful applications of these protocols in a ...variety of well-isolated micro-systems, including microwave photons and superconducting qubits. However, stabilizing the quantum state of a tangibly massive object, such as a mechanical oscillator, remains very challenging: the main obstacle is environmental decoherence, which places stringent requirements on the timescale in which the state must be measured. Here we describe a position sensor that is capable of resolving the zero-point motion of a solid-state, 4.3-megahertz nanomechanical oscillator in the timescale of its thermal decoherence, a basic requirement for real-time (Markovian) quantum feedback control tasks, such as ground-state preparation. The sensor is based on evanescent optomechanical coupling to a high-Q microcavity, and achieves an imprecision four orders of magnitude below that at the standard quantum limit for a weak continuous position measurement--a 100-fold improvement over previous reports--while maintaining an imprecision-back-action product that is within a factor of five of the Heisenberg uncertainty limit. As a demonstration of its utility, we use the measurement as an error signal with which to feedback cool the oscillator. Using radiation pressure as an actuator, the oscillator is cold damped with high efficiency: from a cryogenic-bath temperature of 4.4 kelvin to an effective value of 1.1 ± 0.1 millikelvin, corresponding to a mean phonon number of 5.3 ± 0.6 (that is, a ground-state probability of 16 per cent). Our results set a new benchmark for the performance of a linear position sensor, and signal the emergence of mechanical oscillators as practical subjects for measurement-based quantum control.
A substantial body of evidence has accumulated linking an increased incidence of cardiovascular disease in patients with acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal ...disease (ESRD). A multitude of novel risk factors related to decreased kidney function might interact with the renal and systemic immune systems involved in renal injury and repair to participate in accelerated atherogenesis (Immune inflammation-Renal injury-Atherosclerosis—the IRA Paradigm). In this review, we will discuss several of these novel risk factors and present the potential for the role of the immune-inflammatory system in accelerated atherosclerosis of kidney disease.
Treating or preventing AKI requires treating or preventing a rise in serum creatinine as well as the immediate and remote clinical consequences associated with AKI. Because a substantial number of ...patients with AKI progress to ESRD, identifying patients likely to progress and halting progression are important goals for treating AKI. Many therapies for AKI are being developed, including RenalGuard Therapy, which aims to maintain high urine output; α-melanocyte-stimulating hormone, with anti-inflammatory and antiapoptotic activities; alkaline phosphatase, which detoxifies proinflammatory substances; novel, small interfering RNA, directed at p53 activation; THR-184, a peptide agonist of bone morphogenetic proteins; removal of catalytic iron, important in free-radical formation; and cell-based therapies, including mesenchymal stem cells in vivo and renal cell therapy in situ. In this review, we explore what treatment of AKI really means, discuss the emerging therapies, and examine the windows of opportunity for treating AKI. Finally, we provide suggestions for accelerating the pathways toward preventing and treating AKI, such as establishing an AKI network, implementing models of catalytic philanthropy, and directing a small percentage of the Medicare ESRD budget for developing therapies to prevent and treat AKI and halt progression of CKD.
When an optical field is reflected from a compliant mirror, its intensity and phase become quantum-correlated due to radiation pressure. These correlations form a valuable resource: the mirror may be ...viewed as an effective Kerr medium generating squeezed states of light, or the correlations may be used to erase backaction from an interferometric measurement of the mirror’s position. To date, optomechanical quantum correlations have been observed in only a handful of cryogenic experiments, owing to the challenge of distilling them from thermomechanical noise. Accessing them at room temperature, however, would significantly extend their practical impact, with applications ranging from gravitational wave detection to chip-scale accelerometry. Here, we observe broadband quantum correlations developed in an optical field due to its interaction with a room-temperature nanomechanical oscillator, taking advantage of its high-cooperativity near-field coupling to an optical microcavity. The correlations manifest as a reduction in the fluctuations of a rotated quadrature of the field, in a frequency window spanning more than an octave below mechanical resonance. This is due to coherent cancellation of the two sources of quantum noise contaminating the measured quadrature—backaction and imprecision. Supplanting the backaction force with an off-resonant test force, we demonstrate the working principle behind a quantum-enhanced “variational” force measurement.
Now also acyclic: The first catalytic, enantioselective, vinylogous Michael reaction of linear, acyclic dienol silyl ethers was achieved. The reaction, based upon the principle of iminium ion ...catalysis, delivered 1,7‐dioxo compounds in one step with good yields, complete regio‐, and excellent enantioselectivity. γ‐Substituted dienol silyl ethers furnished products with two new stereogenic centers with good diastereoselectivity. Ms=mesityl, PNBA=para‐nitrobenzoic acid.
Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts ...as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of
genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.
Autophagy has emerged as another major "programmed" mechanism to control life and death much like "programmed cell death" is for apoptosis in eukaryotes. We examined the expression of autophagic ...proteins and formation of autophagosomes during progression of cisplatin injury to renal tubular epithelial cells (RTEC). Autophagy was detected as early as 2-4 h after cisplatin exposure as indicated by induction of LC3-I, conversion of LC3-I to LC3-II protein, and upregulation of Beclin 1 and Atg5, essential markers of autophagy. The appearance of cisplatin-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in RTEC provided further evidence for autophagy. The autophagy inhibitor 3-methyladenine blocked punctated staining of autophagosomes. The staining of normal cells with acridine orange displayed green fluorescence with cytoplasmic and nuclear components in normal cells but displayed considerable red fluorescence in cisplatin-treated cells, suggesting formation of numerous acidic autophagolysosomal vacuoles. Autophagy inhibitors LY294002 or 3-methyladenine or wortmannin inhibited the formation of autophagosomes but induced apoptosis after 2-4 h of cisplatin treatment as indicated by caspase-3/7 and -6 activation, nuclear fragmentation, and cell death. This switch from autophagy to apoptosis by autophagic inhibitors further suggests that the preapoptotic lag phase after treatment with cisplatin is mediated by autophagy. At later stages of cisplatin injury, apoptosis was also found to be associated with autophagy, as autophagic inhibitors and inactivation of autophagy proteins Beclin 1 and Atg5 enhanced activation of caspases and apoptosis. Our results demonstrate that induction of autophagy mounts an adaptive response, suppresses cisplatin-induced apoptosis, and prolongs survival of RTEC.
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