Noninvasive In Vivo Imaging of Diabetes-Induced Renal Oxidative Stress and Response to Therapy Using Hyperpolarized 13C Dehydroascorbate Magnetic Resonance

Keshari, Kayvan R.; Wilson, David M.; Sai, Victor; Bok, Robert; Jen, Kuang-Yu; Larson, Peder E. Z.; Criekinge, Mark Van; Kurhanewicz, John; Wang, Zhen J.

doi:10.2337/db13-1829

Cited by 61 publications

(65 citation statements)

References 51 publications

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“…Oxidative stress contributes to the pathogenesis of diabetic nephropathy [33] and the KEAP1–NRF2 system even governs antioxidant redox signalling to prevent the initiation of diabetes mellitus [34, 35]. We and others have demonstrated the beneficial role of NRF2 induction in the prevention of diabetic nephropathy [2, 36].…”

Section: Discussionmentioning

confidence: 99%

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

Kong

Tan

et al. 2016

Diabetologia

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Aims/hypothesis Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy. Methods Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]). Results Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis. Conclusions/interpretation The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21.

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Section: Discussionmentioning

confidence: 99%

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

Kong

Tan

et al. 2016

Diabetologia

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“…Dehydroascorbic acid (DHA), the oxidized form of AA, was developed as an investigative probe to measure chemical reduction potential. An increased amount of [1- 13 C] DHA reduction to [1- 13 C] AA in vivo was found to correlate with increased intracellular antioxidant concentrations in a diabetic mouse model [48], indicating HP [1- 13 C] DHA reduction may assess the altered redox capacity in disease and may also hold the potential to monitor treatment response. The long T 1 ’s observed for [1- 13 C] DHA (56 s) are favorable for clinical field strengths but [1- 13 C] DHA still suffers from low overall liquid-state polarization (~6%).…”

Section: Physical and Biological Properties Of Polarized Agentsmentioning

confidence: 99%

Magnetic resonance imaging with hyperpolarized agents: methods and applications

et al. 2017

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In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into 1) a brief introduction, 2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, 3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, 4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study 5) metabolic pathways in cancer and cardiac disease and 6) lung function in both pre-clinical and clinical research studies, 7) some future directions and challenges, and 8) an overall summary.

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“…Using a hyperpolarized [1- 13 C]pyruvate, Laustsen et al has shown that reduction of inspired oxygen increases renal lactate and alanine formation in diabetic mice, while this effect is not observed in non-diabetic controls [41, 42], indicating that reduced oxygen availability alters renal energy metabolism in diabetes. Further, Keshari et al has assessed the oxidative stress in diabetic mouse kidneys using a hyperpolarized [1- 13 C] dehydroascorbate (DHA), a new endogenous redox sensor, and shown that redox capacity is decreased in diabetic kidneys prior to histological evidence of nephropathy and that angiotensin converting enzyme inhibition restores the renal redox status in diabetic mice [43]. Further, Clatworthy et al has assessed renal fumarate metabolism in folic acid-induced AKI mice using this technique and shown that renal production of [1,4- 13 C 2 ]malate, a fumarate metabolite, is increased in early phase of AKI [44].…”

Section: Assessment Of Renal Metabolismmentioning

confidence: 99%

Current MRI techniques for the assessment of renal disease

Takahashi

Wang²,

Quarles³

2015

Current Opinion in Nephrology and Hypertension

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Purpose of review Over the past decade a variety of magnetic resonance imaging (MRI) methods have been developed and applied to many kidney diseases. These MRI techniques show great promise, enabling the noninvasive assessment of renal structure, function, and injury in individual subjects. This review will highlight current applications of functional MRI techniques for the assessment of renal disease and discuss future directions. Recent findings Many pathological (functional and structural) changes or factors in renal disease can be assessed by advanced MRI techniques. These include renal vascular structure and function (contrast-enhanced MRI, arterial spin labeling), tissue oxygenation (blood oxygen level-dependent MRI), renal tissue injury and fibrosis (diffusion or magnetization transfer imaging, MR elastography), renal metabolism (chemical exchange saturation transfer, spectroscopic imaging), nephron endowment (cationic-contrast imaging), sodium concentration (23Na-MRI), and molecular events (targeted-contrast imaging). Summary Current advances in MRI techniques have enabled the non-invasive investigation of renal disease. Further development, evaluation, and application of the MRI techniques should facilitate better understanding and assessment of renal disease and the development of new imaging biomarkers, enabling the intensified treatment to high-risk populations and a more rapid interrogation of novel therapeutic agents and protocols.

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Noninvasive In Vivo Imaging of Diabetes-Induced Renal Oxidative Stress and Response to Therapy Using Hyperpolarized 13C Dehydroascorbate Magnetic Resonance

Cited by 61 publications

References 51 publications

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21

Magnetic resonance imaging with hyperpolarized agents: methods and applications

Current MRI techniques for the assessment of renal disease

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