Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease

Sharma, Kumar; Karl, Bethany; Mathew, Anna V.; Gangoiti, Jon A.; Wassel, Christina L.; Saito, Rintaro; Pu, Minya; Sharma, Shoba; You, Young Hyun; Wang, Lin; Diamond‐Stanic, Maggie; Lindenmeyer, Maja T.; Forsblom, Carol; Wu, Wei; Ix, Joachim H.; Ideker, Trey; Kopp, Jeffrey B.; Nigám, Sanjay K.; Cohen, Clemens D.; Groop, Per Henrik; Barshop, Bruce A.; Natarajan, Loki; Nyhan, William L.; Naviaux, Robert K.

doi:10.1681/asn.2013020126

Cited by 468 publications

(468 citation statements)

References 27 publications

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“…Using these W. Ding : R. H. Mak (*) noninvasive biomarkers, these authors were able to predict, several months in advance and with 94 % precision, the clinical evolution of neonates with ureteropelvic junction obstruction [5]. Sharma et al used metabolomics approaches to quantify 94 urine metabolites in screening and validation cohorts of patients with diabetes mellitus (DM) and CKD (DM+CKD), in patients with DM without CKD (DM − CKD), and in healthy controls [6]. Comparison of all these metabolites with the levels in healthy controls revealed that 13 metabolites were significantly reduced in the (DM+CKD) cohorts (P≤ 0.001) and that 12 of these 13 remained significant when compared with the (DM − CKD) cohort.…”

Section: Biomarkers Of Renal Injurymentioning

confidence: 99%

“…Comparison of all these metabolites with the levels in healthy controls revealed that 13 metabolites were significantly reduced in the (DM+CKD) cohorts (P≤ 0.001) and that 12 of these 13 remained significant when compared with the (DM − CKD) cohort. Analysis of the bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism, suggesting global suppression of mitochondrial activity in diabetic kidney disease [6].…”

Section: Biomarkers Of Renal Injurymentioning

confidence: 99%

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Early markers of obesity-related renal injury in childhood

Ding

Mak

2014

Pediatr Nephrol

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Childhood obesity has become a global epidemic. Recent epidemiological data suggest that obesity is associated with increased risk of renal injury in children. The onset of obesity-associated renal disease is insidious and asymptomatic, so early markers will be extremely useful in its prevention and treatment. Biomarker discovery can be focused on unbiased or biased (candidate) approaches. Unbiased approaches using innovative technologies, such as proteomics and metabolomics, have uncovered candidates that are emerging as plausible biomarkers for such renal disorders as obstructive uropathy and diabetic nephropathy. Biased approaches are based on hypotheses related to glomerular or tubular injury pathophysiology in obesity. Goknar et al. (Pediatric Nephrology 2014; doi: 10.1007/s00467-014-2829 recently evaluated early urine renal injury markers, namely, microalbuminuria, N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin, and kidney injury molecule (KIM)-1, in obese children. They reported that obese children had higher urinary NAG and KIM-1 levels than healthy controls. Longitudinal observation studies are needed to evaluate whether these tubular damage markers are useful as early markers of renal injury in obese children.

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Section: Biomarkers Of Renal Injurymentioning

confidence: 99%

Section: Biomarkers Of Renal Injurymentioning

confidence: 99%

Early markers of obesity-related renal injury in childhood

Ding

Mak

2014

Pediatr Nephrol

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“…5,6 Although the pathogenesis of DKD still remains unclear, recent studies in animals and humans have led to an emerging concept that mitochondrial dysfunctions, which are pivotal events, lead to activation of various cellular processes and aberrant signaling in different cell types of the kidney. [7][8][9] Mitochondria are dynamic organelles that constantly undergo fusion and fission cycles to maintain a balance of cellular reticular network and mitochondrial turnover. 10 Their dynamics are regulated by profission proteins (Drp1 and Fis1) and profusion mediators (Mfn1/2 and OPA1).…”

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confidence: 99%

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

234

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Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under highglucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/ mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or D-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of D-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, D-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest D-glucarate as a potential therapeutic agent for the amelioration of DKD.

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“…Most currently used biochemical markers of renal function fall into this category (e.g., creatinine, urea, uric acid, and cystatin C). They represent not only the active biologic processes, but they are also thought to have possible functional roles in health and disease (17). Metabolomics datasets can be generated using high-field nuclear magnetic resonance spectroscopy or mass spectrometry to separate and detect metabolites followed by data processing and bioinformatics analyses for identification (18,19).…”

Section: Metabolomicsmentioning

confidence: 99%

Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology

Mariani

Pendergraft

Kretzler

2016

CJASN

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Advances in biomedical research allow for the capture of an unprecedented level of genetic, molecular, and clinical information from large patient cohorts, where the quest for precision medicine can be pursued. An overarching goal of precision medicine is to integrate the large-scale genetic and molecular data with deep phenotypic information to identify a new mechanistic disease classification. This classification can ideally be used to meet the clinical goal of the right medication for the right patient at the right time. Glomerular disease presents a formidable challenge for precision medicine. Patients present with similar signs and symptoms, which cross the current disease categories. The diseases are grouped by shared histopathologic features, but individual patients have dramatic variability in presentation, progression, and response to therapy, reflecting the underlying biologic heterogeneity within each glomerular disease category. Despite the clinical challenge, glomerular disease has several unique advantages to building multilayered datasets connecting genetic, molecular, and structural information needed to address the goals of precision medicine in this population. Kidney biopsy tissue, obtained during routine clinical care, provides a direct window into the molecular mechanisms active in the affected organ. In addition, urine is a biofluid ideally suited for repeated measurement from the diseased organ as a liquid biopsy with potential to reflect the dynamic state of renal tissue. In our review, current approaches for large-scale data generation and integration along the genotype-phenotype continuum in glomerular disease will be summarized. Several successful examples of this integrative biology approach within glomerular disease will be highlighted along with an outlook on how achieving a mechanistic disease classification could help to shape glomerular disease research and care in the future.

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Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease

Cited by 468 publications

References 27 publications

Early markers of obesity-related renal injury in childhood

Early markers of obesity-related renal injury in childhood

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology

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