Transcriptomic analysis and plasma metabolomics in Aldh16a1 -null mice reveals a potential role of ALDH16A1 in renal function

Charkoftaki, Georgia; Chen, Ying; Han, Ming; Sandoval, Monica; Yu, Xiaoqing; Zhao, Hongyu; Orlicky, David J.; Thompson, David C.; Vasiliou, Vasilis

doi:10.1016/j.cbi.2017.02.013

Cited by 19 publications

(9 citation statements)

References 46 publications

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“…(ii) Aldehyde dehydrogenase 16 family member A1 (ALDH16A1) is nominally up-regulated under paraquat exposure (logFC: 1.47, P: 2.0e−2; adjusted P 2.5e−1). Although a member of the aldehyde dehydrogenase family, ALDH16A1 contains aldehyde dehydrogenase domains that are thought to be inactive 31 , and its function in the heart remains unknown. It is ubiquitously expressed and has no clear co-expressed genes across human tissues, but previous ChIP-seq data has shown that its promoter region may bind to STAT3 32 , which is also upregulated in the data (logFC: 0.65, P: 3.8e−4; adjusted P: 2.9e−2).…”

Section: Resultsmentioning

confidence: 99%

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Dostal

Wood

Thomas

et al. 2020

Sci Rep

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The heart is sensitive to oxidative damage but a global view on how the cardiac proteome responds to oxidative stressors has yet to fully emerge. Using quantitative tandem mass spectrometry, we assessed the effects of acute exposure of the oxidative stress inducer paraquat on protein expression in mouse hearts. We observed widespread protein expression changes in the paraquat-exposed heart especially in organelle-containing subcellular fractions. During cardiac response to acute oxidative stress, proteome changes are consistent with a rapid reduction of mitochondrial metabolism, coupled with activation of multiple antioxidant proteins, reduction of protein synthesis and remediation of proteostasis. In addition to differential expression, we saw evidence of spatial reorganizations of the cardiac proteome including the translocation of hexokinase 2 to more soluble fractions. Treatment with the antioxidants Tempol and MitoTEMPO reversed many proteomic signatures of paraquat but this reversal was incomplete. We also identified a number of proteins with unknown function in the heart to be triggered by paraquat, suggesting they may have functions in oxidative stress response. Surprisingly, protein expression changes in the heart correlate poorly with those in the lung, consistent with differential sensitivity or stress response in these two organs. The results and data set here could provide insights into oxidative stress responses in the heart and avail the search for new therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Dostal

Wood

Thomas

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…(ii) Aldehyde dehydrogenase 16 family member A1 (ALDH16A1) is nominally up-regulated under paraquat exposure (logFC: 1.47, P: 2.0e-2; adjusted P 2.5e-1). Although a member of the aldehyde dehydrogenase family, ALDH16A1 contains aldehyde dehydrogenase domains that are thought to be inactive [26], and its function in the heart remains unknown. It is ubiquitously expressed and has no clear co-expressed genes across human tissues, but previous ChIP-seq data has shown that its promoter region may bind to STAT3 [27], which is also upregulated in the data (logFC: 0.65, P: 3.8e-4; adjusted P: 2.9e-2).…”

Section: Resultsmentioning

confidence: 99%

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Dostal

Wood

Thomas

et al. 2020

Preprint

View full text Add to dashboard Cite

The heart is sensitive to oxidative damage but a global view on how the cardiac proteome responds to oxidative stressors has yet to fully emerge. Using quantitative tandem mass spectrometry, we assessed the effects of acute exposure of the oxidative stress inducer paraquat on protein expression in mouse hearts. We observed widespread protein expression changes in the paraquat-exposed heart especially in organelle-containing subcellular fractions. During cardiac response to acute oxidative stress, proteome changes are consistent with a rapid reduction of mitochondrial metabolism, coupled with activation of multiple antioxidant proteins, reduction of protein synthesis and remediation of proteostasis. In addition to differential expression, we saw evidence of spatial reorganizations of the cardiac proteome including the translocation of hexokinase 2 to more soluble fractions. Treatment with the antioxidants Tempol and MitoTEMPO reversed many proteomic signatures of paraquat but this reversal was incomplete. We also identified a number of proteins with unknown function in the heart to be triggered by paraquat, suggesting they may have functions in oxidative stress response. Surprisingly, protein expression changes in the heart correlate poorly with those in the lung, consistent with differential sensitivity or stress response in these two organs. The results provide insights into oxidative stress responses in the heart and may avail the search for new therapeutic targets.

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“…SLC16A9 is ubiquitously expressed and is especially expressed at a high level in the kidney [19,20]. ALDH16A1 gene is associated with serum uric acid levels and gout, and RNA sequencing in the kidney of wild-type (WT) and Aldh16a1 knockout (KO) mice revealed changes in Slc16a9 are localized to the apical membrane of the proximal convoluted tubule cells and influence uric acid homeostasis [49]. ese findings suggested the potential role of SLC16A9 in the aetiology of gout.…”

Section: Discussionmentioning

confidence: 97%

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

Huang

Sun

Zhang

et al. 2020

BioMed Research International

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Gout is a common inflammatory arthritis triggered by monosodium urate deposition after longstanding hyperuricemia. In the general community, the disease is largely polygenic in genetic architecture, with many polymorphisms having been identified in gout or urate-associated traits. In a small proportion of cases, rare high penetrant mutations associated with monogenic segregation of the disease in families have been demonstrated to be disease causative. In this study, we recruited a two-generation pedigree with early-onset gout. To elucidate the genetic predisposition, whole-exome sequencing (WES) was performed. After comprehensive variant analyses and cosegregation testing, we identified a missense variant (c.277C>A, p.L93M) in SLC16A9, an extremely rare variant in genetic databases. Moreover, in silico assessments showed strong pathogenicity. This variant cosegregated with the disease phenotype perfectly in the family and is located in a highly conserved functional domain. A few studies supported our results of the association between SLC16A9 and gout and serum urate levels. In conclusion, we provide the first evidence for the association of rare missense in SLC16A9 with early-onset gout. These findings not only expand our current understanding of gout but also may have further implications for the treatment and prevention of gout.

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Transcriptomic analysis and plasma metabolomics in Aldh16a1 -null mice reveals a potential role of ALDH16A1 in renal function

Cited by 19 publications

References 46 publications

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Proteomic signatures of acute oxidative stress response to paraquat in the mouse heart

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

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