Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease
Kumar Sharma,Bethany Karl,Anna V. Mathew,Jon A. Gangoiti,Christina L. Wassel,Rintaro Saito,Minya Pu,Shoba Sharma,Young Hyun You,Lin Wang,Maggie Diamond-Stanic,Maja T. Lindenmeyer,Carol Forsblom,Wei Wu,Joachim H. Ix,Trey Ideker,Jeffrey B. Kopp,Sanjay K. Nigam,Clemens D. Cohen,Per-Henrik Groop,Per-Henrik Groop,Bruce A. Barshop,Loki Natarajan,William L. Nyhan,Robert K. Naviaux +24 more
TLDR
It is concluded that urine metabolomics is a reliable source for biomarkers of diabetic complications, and the data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.Abstract:
Diabetic kidney disease is the leading cause of ESRD, but few biomarkers of diabetic kidney disease are available. This study used gas chromatography-mass spectrometry 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. Compared with levels in healthy controls, 13 metabolites were significantly reduced in the DM+CKD cohorts (P≤0.001), and 12 of the 13 remained significant when compared with the DM-CKD cohort. Many of the differentially expressed metabolites were water-soluble organic anions. Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduced levels of urinary organic acids, and human kidney tissue from patients with diabetic nephropathy demonstrated lower gene expression of OAT1 and OAT3. Analysis of bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism and suggested global suppression of mitochondrial activity in diabetic kidney disease. Supporting this analysis, human diabetic kidney sections expressed less mitochondrial protein, urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1α (a master regulator of mitochondrial biogenesis). We conclude that urine metabolomics is a reliable source for biomarkers of diabetic complications, and our data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.read more
Citations
More filters
Journal ArticleDOI
Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis
Jay S. Skyler,George L. Bakris,Ezio Bonifacio,Tamara Darsow,Robert H. Eckel,Leif Groop,Per-Henrik Groop,Per-Henrik Groop,Yehuda Handelsman,Richard A. Insel,Chantal Mathieu,Allison T. McElvaine,Jerry P. Palmer,Alberto Pugliese,Desmond A. Schatz,Jay M. Sosenko,John P.H. Wilding,Robert E. Ratner +17 more
TL;DR: A structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment is recommended.
Journal ArticleDOI
Diabetic kidney disease
Merlin C. Thomas,Michael Brownlee,Katalin Susztak,Kumar Sharma,Karin Jandeleit-Dahm,Sophia Zoungas,Peter Rossing,Per-Henrik Groop,Mark E. Cooper +8 more
TL;DR: What is now known about the molecular pathogenesis of CKD in patients with diabetes and the key pathways and targets implicated in its progression are summarized and the opportunities to develop new interventions through urgently needed investment in dedicated and focused research are explored.
Journal ArticleDOI
What do drug transporters really do
TL;DR: Evidence is discussed for the roles of ABC and SLC transporters in the handling of diverse substrates, including metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters, which may help to clarify disease mechanisms, drug–metabolite interactions and drug effects relevant to diabetes, chronic kidney disease, metabolic syndrome, hypertension, gout, liver disease, neuropsychiatric disorders, inflammatory syndromes and organ injury.
Journal ArticleDOI
AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
Laura L. Dugan,Young Hyun You,Young Hyun You,Sameh S. Ali,Maggie Diamond-Stanic,Maggie Diamond-Stanic,Satoshi Miyamoto,Satoshi Miyamoto,Anne-Emilie Decleves,Anne-Emilie Decleves,Aleksander Andreyev,Tammy Quach,Tammy Quach,San Ly,San Ly,Grigory Shekhtman,William Nguyen,Andre Chepetan,Thuy Le,Lin Wang,Ming Xu,Kacie P. Paik,Agnes B. Fogo,Benoit Viollet,Anne N. Murphy,Frank C. Brosius,Robert K. Naviaux,Kumar Sharma,Kumar Sharma +28 more
TL;DR: It is demonstrated that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.
Journal ArticleDOI
The Organic Anion Transporter (OAT) Family: A Systems Biology Perspective
Sanjay K. Nigam,Kevin T. Bush,Gleb Martovetsky,Sun-Young Ahn,Henry C. Liu,Erin Richard,Vibha Bhatnagar,Wei Wu +7 more
TL;DR: According to the "Remote Sensing and Signaling Hypothesis," which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids.
References
More filters
Journal ArticleDOI
Controlling the false discovery rate: a practical and powerful approach to multiple testing
Yoav Benjamini,Yosef Hochberg +1 more
TL;DR: In this paper, a different approach to problems of multiple significance testing is presented, which calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate, which is equivalent to the FWER when all hypotheses are true but is smaller otherwise.
Journal ArticleDOI
A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance
Christopher B. Newgard,Jie An,James R. Bain,Michael J. Muehlbauer,Robert Stevens,Lillian F. Lien,Andrea M. Haqq,Svati H. Shah,Michelle Arlotto,Cris A. Slentz,James Rochon,Dianne Gallup,Olga Ilkayeva,Brett R. Wenner,William S. Yancy,Howard Eisenson,Gerald Musante,Richard S. Surwit,David S. Millington,Mark D. Butler,Laura P. Svetkey +20 more
TL;DR: Findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.
Journal ArticleDOI
Metabolite profiles and the risk of developing diabetes
Thomas J. Wang,Martin G. Larson,Martin G. Larson,Ramachandran S. Vasan,Ramachandran S. Vasan,Susan Cheng,Susan Cheng,Susan Cheng,Eugene P. Rhee,Eugene P. Rhee,Elizabeth L. McCabe,Elizabeth L. McCabe,Gregory D. Lewis,Gregory D. Lewis,Caroline S. Fox,Caroline S. Fox,Paul F. Jacques,Céline Fernandez,Christopher J. O'Donnell,Christopher J. O'Donnell,Christopher J. O'Donnell,Stephen A Carr,Vamsi K. Mootha,Vamsi K. Mootha,Jose C. Florez,Jose C. Florez,Amanda Souza,Olle Melander,Clary B. Clish,Robert E. Gerszten,Robert E. Gerszten +30 more
TL;DR: Findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
Journal ArticleDOI
Metabolite profiles and the risk of developing diabetes
Wang T J,Larson M G,Vasan R S,Susan Cheng,Rhee E P,Elizabeth L. McCabe,Lewis G D,Fox C S,Jacques P F,Céline Fernandez,ODonnell C J,Carr S A,Mootha V K,Florez J C,Amanda Souza,Olle Melander,Clish C B,Gerszten R E +17 more
Journal ArticleDOI
Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density.
Romain Barrès,Megan E. Osler,Jie Yan,Anna Rune,Tomas Fritz,Kenneth Caidahl,Anna Krook,Anna Krook,Juleen R. Zierath,Juleen R. Zierath +9 more
TL;DR: Using whole-genome promoter methylation analysis of skeletal muscle from normal glucose-tolerant and type 2 diabetic subjects, cytosine hypermethylation of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) in diabetic subjects is identified and link DNMT3B to the acute fatty-acid-induced non-CpG methylation of PGC- 1alpha promoter.
Related Papers (5)
AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
Laura L. Dugan,Young Hyun You,Young Hyun You,Sameh S. Ali,Maggie Diamond-Stanic,Maggie Diamond-Stanic,Satoshi Miyamoto,Satoshi Miyamoto,Anne-Emilie Decleves,Anne-Emilie Decleves,Aleksander Andreyev,Tammy Quach,Tammy Quach,San Ly,San Ly,Grigory Shekhtman,William Nguyen,Andre Chepetan,Thuy Le,Lin Wang,Ming Xu,Kacie P. Paik,Agnes B. Fogo,Benoit Viollet,Anne N. Murphy,Frank C. Brosius,Robert K. Naviaux,Kumar Sharma,Kumar Sharma +28 more
Metabolite profiles and the risk of developing diabetes
Thomas J. Wang,Martin G. Larson,Martin G. Larson,Ramachandran S. Vasan,Ramachandran S. Vasan,Susan Cheng,Susan Cheng,Susan Cheng,Eugene P. Rhee,Eugene P. Rhee,Elizabeth L. McCabe,Elizabeth L. McCabe,Gregory D. Lewis,Gregory D. Lewis,Caroline S. Fox,Caroline S. Fox,Paul F. Jacques,Céline Fernandez,Christopher J. O'Donnell,Christopher J. O'Donnell,Christopher J. O'Donnell,Stephen A Carr,Vamsi K. Mootha,Vamsi K. Mootha,Jose C. Florez,Jose C. Florez,Amanda Souza,Olle Melander,Clary B. Clish,Robert E. Gerszten,Robert E. Gerszten +30 more