A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease

Taylor, Sandra L.; Ganti, Sheila; Bukanov, Nikolay O.; Chapman, Arlene B.; Fiehn, Oliver; Osier, Michael V.; Kim, Kyoungmi; Weiss, Robert H.

doi:10.1152/ajprenal.00722.2009

Cited by 52 publications

(42 citation statements)

References 52 publications

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“…These data suggest that recessive PKD cells are reprogrammed to require exogenous glutamine for production of glutaminesourced 2-HG that may ultimately result in augmented RTE cell survival or proliferation. While there have been several studies examining the metabolic profile of ADPKD, including one from our laboratory (27,29), this study is the first to evaluate nontargeted metabolomics in recessive PKD. Our finding that glutamine addiction also occurs in a human ADPKD epithelial cell line suggests the possibility of a more general phenomenon such that targeting the glutamine pathway, for example, using GLS inhibitors, may be a novel therapeutic approach for renal cystic disease.…”

Section: Discussionmentioning

confidence: 99%

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate

Hwang

Kim

Rand

et al. 2015

American Journal of Physiology-Renal Physiology

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LM, Weiss RH. The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate. Am J Physiol Renal Physiol 309: F492-F498, 2015. First published July 8, 2015 doi:10.1152/ajprenal.00238.2015.-Since polycystic kidney disease (PKD) was first noted over 30 years ago to have neoplastic parallels, there has been a resurgent interest in elucidating neoplasia-relevant pathways in PKD. Taking a nontargeted metabolomics approach in the B6(Cg)-Cys1 cpk/ J (cpk) mouse model of recessive PKD, we have now characterized metabolic reprogramming in these tissues, leading to a glutamine-dependent TCA cycle shunt toward total 2-hydroxyglutarate (2-HG) production in cpk compared with B6 wild-type kidney tissue. After confirmation of increased 2-HG expression in immortalized collecting duct cpk cells as well as in human autosomal recessive PKD tissue using targeted analysis, we show that the increase in 2-HG is likely due to glutamine-sourced ␣-ketoglutarate. In addition, cpk cells require exogenous glutamine for growth such that inhibition of glutaminase-1 decreases cell viability as well as proliferation. This study is a demonstration of the striking parallels between recessive PKD and cancer metabolism. Our data, once confirmed in other PKD models, suggest that future therapeutic approaches targeting this pathway, such as using glutaminase inhibitors, have the potential to open novel treatment options for renal cystic disease. ARPKD; glutamine; metabolomics; oncometabolite; reprogramming THE POLYCYSTIC KIDNEY DISEASES (PKD) are disorders characterized by, among other signaling events, dysregulated renal tubular epithelial (RTE) cell proliferation. While the concept that PKD is a "neoplasia in disguise" was initially suggested by Grantham in 1990 (9), it is becoming increasingly clear that the cystic renal diseases have marked biochemical similarities with many aspects of the malignant process (22). Consequently, PKD is now being investigated in the context of tumor metabolism with an eye toward discovery of new therapies and/or repurposing of currently approved or pipeline oncology drugs. Indeed, recent studies in our and other laboratories have shown connections between the cyclin-dependent kinases (1,17,18) and nuclear transport (26) inhibitors in PKD, as well as a striking parallel of metabolic reprogramming related to glycolysis and the Warburg effect, which was shown to occur in an autosomal dominant PKD model (21).Given the current emphasis on the metabolic changes associated with oncogenesis, and since we have successfully utilized metabolomics to discover biomarkers and altered metabolic pathways in renal cell carcinoma (RCC) (8, 30), we took a nontargeted metabolomics approach to compare cancer with autosomal recessive PKD (ARPKD) metabolic pathways. We evaluated the three "matrices" (kidney tissue, serum, and urine) in the B6(Cg)-Cys1 cpk/ J (cpk) mouse model of recessive PKD (10) and then validated the changes in human ARPKD tissue and unaffected contro...

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Section: Discussionmentioning

confidence: 99%

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate

Hwang

Kim

Rand

et al. 2015

American Journal of Physiology-Renal Physiology

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“…This is unfortunate, because early diagnosis of ADPKD in at-risk patients might lead to interventions (some in the pipeline) that can slow its progression. Our laboratory has utilized the Jck cystic mouse model (which is no longer the ideal model for ADPKD) in a metabolic investigation of potential urinary biomarkers of cystic kidney disease; 14 we showed that the cystic mouse can be discriminated from its wild-type counterpart by urine analysis alone. At day 26 of life, before there is serological evidence of kidney dysfunction, affected mice are distinguishable by urine metabolomic analysis; this finding persists through 45 d until 64 d, at which time body weight differences confound the results.…”

Section: Applications Of Metabolomics To Kidney Diseasementioning

confidence: 99%

Applications of Metabolomics for Kidney Disease Research

Wettersten

Weiss

2013

Organogenesis

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Metabolomics is one of the relative newcomers of the omics techniques and is likely the one most closely related to actual real-time disease pathophysiology. Hence, it has the power to yield not only specific biomarkers but also insight into the pathophysiology of disease. Despite this power, metabolomics as applied to kidney disease is still in its early adolescence and has not yet reached the mature stage of clinical application, i.e., specific biomarker and therapeutic target discovery. On the other hand, the insight gained from hints into what makes these diseases tick, as is evident from the metabolomics pathways which have been found to be altered in kidney cancer, are now beginning to bear fruit in leading to potential therapeutic targets. It is quite likely that, with greater numbers of clinical materials and with more investigators jumping into the field, metabolomics may well change the course of kidney disease research.

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“…AN ELEGANT STUDY (7) is contained in an issue of the American Journal of Physiology-Renal Physiology that discovers potential urinary biomarkers that are relatively common metabolites from various metabolic pathways. While this author is not an expert in metabolism, the fact that purine metabolism was shown to be upregulated in the study evoked a "déjà vu all over again" response from this author to the findings.…”

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“…Indeed, the galactose metabolic pathway is also affected, yielding allantoic acid as another candidate biomarker (7). Other metabolites derived from purine and galactose metabolism were also upregulated along with a handful of other candidate biomarkers.…”

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Compelling “metabolomic” biomarkers may signal PKD pathogenesis

Schwiebert¹

2010

American Journal of Physiology-Renal Physiology

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AN ELEGANT STUDY (7) is contained in an issue of the American Journal of Physiology-Renal Physiology that discovers potential urinary biomarkers that are relatively common metabolites from various metabolic pathways. While this author is not an expert in metabolism, the fact that purine metabolism was shown to be upregulated in the study evoked a "déjà vu all over again" response from this author to the findings. While performing academic research on extracellular purinergic signaling and PKD, our laboratory performed experiments on primary human noncystic and cystic kidney epithelial cells and showed that both basal and stimulated ATP secretion (release, efflux) were potentiated in cystic cell cultures grown on plastic or on permeable filter supports versus companion noncystic cell controls (9). We also showed high (nanomolar to micromolar) amounts of ATP in flash-frozen cyst fluid tapped from human ADPKD cysts in a subset of the samples to complement and show in vivo relevance for our work (9). We concluded that this could be due to an upregulation in secretory ATP transport and/or exocytosis of ATP-filled granules. Alternatively, we conceded that this observation might also be reflective of enhanced metabolism, possibly derived from enhanced proliferation of cystic cells. We also made the argument then that trapped ATP and its metabolites (adenosine) would be detrimental to the progression of PKD in two ways. First, ATP and adenosine are known mitogens or comitogens for many cell types derived from different tissues. Second, ATP and adenosine stimulate salt and fluid secretion across epithelia via different signaling mechanisms. We also hypothesized that ATP's metabolites (especially adenosine) might also accumulate in high amounts and also be detrimental for the same reasons. However, we had no way to measure adenosine easily at the time and not enough sample with which to do HPLC measurements.In follow-on papers from our laboratory (3, 5, 6) as well as in studies on liver and bile duct by Doctor and coworkers (1) and in studies in Madin-Darby canine kidney cell cysts by Turner and coworkers (8), it has been clearly demonstrated that ATP secretion mechanisms, ATP receptors (P2X receptor channels and P2Y G protein-coupled receptors), and ion and water channels stimulated by autocrine and paracrine extracellular nucleotide and nucleoside signaling are present in human and mouse cystic epithelial cells. Normally, this signaling would take place either in the tubular fluid or interstitium, but it would either be carried downstream to other nephron segments or it would diffuse away with the interstitium (3). Extracellular ATP is also quickly metabolized into ADP, 5' AMP, and adenosine by ecto-ATPases, ecto-ADPases, and ecto-nucleotidases. Robson, Friedman, Kishore and colleagues, as well as other have mapped many of these enzymes elegantly along the nephron (2, 4). However, upon cyst encapsulation before cyst expansion, extracellular ATP and adenosine signaling would continue to occur. As a consequence, it might t...

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A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease

Abstract: RH. A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease.

Cited by 52 publications

References 52 publications

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate

Applications of Metabolomics for Kidney Disease Research

Compelling “metabolomic” biomarkers may signal PKD pathogenesis

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