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Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy.

Zhao YY, Wang HL, Cheng XL, Wei F, Bai X, Lin RC, Vaziri ND - Sci Rep (2015)

Bottom Line: Data obtained on weeks 8 to 24 revealed progressive tubulointerstitial fibrosis, inflammation, renal dysfunction, activation of NF-κB, TGF-β, and oxidative pathways, impaired Nrf2 system, and profound changes in lipid metabolites including numerous PC, lysoPC, PE, lysoPE, ceramides and triglycerides.In conclusion, exposure to AAI results in dynamic changes in kidney tissue fatty acid, phospholipid, and glycerolipid metabolisms prior to and after the onset of detectable changes in renal function or histology.These findings point to participation of altered tissue lipid metabolism in the pathogenesis of AAN.

View Article: PubMed Central - PubMed

Affiliation: 1] Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, the College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China [2] Division of Nephrology and Hypertension, School of Medicine, University of California, Irvine, MedSci 1, C352, UCI Campus, Irvine, California, 92897, USA.

ABSTRACT
Alternative medicines are commonly used for the disease prevention and treatment worldwide. Aristolochic acid (AAI) nephropathy (AAN) is a common and rapidly progressive interstitial nephropathy caused by ingestion of Aristolochia herbal medications. Available data on pathophysiology and molecular mechanisms of AAN are limited and were explored here. SD rats were randomized to AAN and control groups. AAN group was treated with AAI by oral gavage for 12 weeks and observed for additional 12 weeks. Kidneys were processed for histological evaluation, Western blotting, and metabolomics analyses using UPLC-QTOF/HDMS. The concentrations of two phosphatidylcholines, two diglycerides and two acyl-carnitines were significantly altered in AAI treated rats at week 4 when renal function and histology were unchanged. Data obtained on weeks 8 to 24 revealed progressive tubulointerstitial fibrosis, inflammation, renal dysfunction, activation of NF-κB, TGF-β, and oxidative pathways, impaired Nrf2 system, and profound changes in lipid metabolites including numerous PC, lysoPC, PE, lysoPE, ceramides and triglycerides. In conclusion, exposure to AAI results in dynamic changes in kidney tissue fatty acid, phospholipid, and glycerolipid metabolisms prior to and after the onset of detectable changes in renal function or histology. These findings point to participation of altered tissue lipid metabolism in the pathogenesis of AAN.

No MeSH data available.


Related in: MedlinePlus

Hierarchical cluster analysis and ROC curves of 16 identified metabolites from AAN and control group in the 8th week.(A) Clustered heat map of only 16 (only appeared at 8 week or after 8 week) out of 69 identified metabolites between 8th week AAN and control groups after observable histological kidney damage and conventional clinical chemistry indications of nephrotoxicity. Heatmap displays of the most significantly changes from 16 metabolites. The colour of each section is proportional to the significance of alternation of metabolites in kidney tissue. Green indicates reduction, red indicates increase compared to control group. Columns represent individual experiments and rows represent each identified metabolites from AAN and control groups in the 8th week. (B) VIP scores with expression heat map from PLS-DA analysis. PLS-DA analysis was constructed with signature metabolites from AAN and control rats. Red and green indicated increased and decreased levels, respectively. (C) PLS-DA based ROC curves of 8 out of 16 identified metabolites for evaluation of AAN with the individual biomarkers. The associated AUC, sensitivity and specificity values were indicated.
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f5: Hierarchical cluster analysis and ROC curves of 16 identified metabolites from AAN and control group in the 8th week.(A) Clustered heat map of only 16 (only appeared at 8 week or after 8 week) out of 69 identified metabolites between 8th week AAN and control groups after observable histological kidney damage and conventional clinical chemistry indications of nephrotoxicity. Heatmap displays of the most significantly changes from 16 metabolites. The colour of each section is proportional to the significance of alternation of metabolites in kidney tissue. Green indicates reduction, red indicates increase compared to control group. Columns represent individual experiments and rows represent each identified metabolites from AAN and control groups in the 8th week. (B) VIP scores with expression heat map from PLS-DA analysis. PLS-DA analysis was constructed with signature metabolites from AAN and control rats. Red and green indicated increased and decreased levels, respectively. (C) PLS-DA based ROC curves of 8 out of 16 identified metabolites for evaluation of AAN with the individual biomarkers. The associated AUC, sensitivity and specificity values were indicated.

Mentions: Hierarchical cluster analysis and the resulting heat map revealed that among the 69 metabolites which were significantly altered at week 8 and beyond. Sixteen of these metabolites were markedly altered in the AAN group at week 8 only (Fig. 5A). The cluster diagram revealed that two groups could be separated completely by these sixteen sleeted metabolites with VIP scores of more than 1.0 (Fig. 5B). To assess the predictive performance of the selected metabolites in the AAN, we calculated the AUC value. Among the above 16 metabolites eight were identified as the top-ranked candidates, with an AUC value of more than 0.85 (Fig. 5C) including phytosphingosine, PC(22:5/14:0), tetracosatetraenoic acid, trimethyltridecanoic acid, lysoPC(16:0), PC(16:0/22:5), TG(14:1/14:0/14:1) and PC(18:2/20:5). As a result, these eight metabolites could potentially be considered as predictive metabolites corresponding with the histological evidence of kidney damage, conventional clinical chemistry and activation of inflammatory, oxidant and fibrotic pathways.


Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy.

Zhao YY, Wang HL, Cheng XL, Wei F, Bai X, Lin RC, Vaziri ND - Sci Rep (2015)

Hierarchical cluster analysis and ROC curves of 16 identified metabolites from AAN and control group in the 8th week.(A) Clustered heat map of only 16 (only appeared at 8 week or after 8 week) out of 69 identified metabolites between 8th week AAN and control groups after observable histological kidney damage and conventional clinical chemistry indications of nephrotoxicity. Heatmap displays of the most significantly changes from 16 metabolites. The colour of each section is proportional to the significance of alternation of metabolites in kidney tissue. Green indicates reduction, red indicates increase compared to control group. Columns represent individual experiments and rows represent each identified metabolites from AAN and control groups in the 8th week. (B) VIP scores with expression heat map from PLS-DA analysis. PLS-DA analysis was constructed with signature metabolites from AAN and control rats. Red and green indicated increased and decreased levels, respectively. (C) PLS-DA based ROC curves of 8 out of 16 identified metabolites for evaluation of AAN with the individual biomarkers. The associated AUC, sensitivity and specificity values were indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528220&req=5

f5: Hierarchical cluster analysis and ROC curves of 16 identified metabolites from AAN and control group in the 8th week.(A) Clustered heat map of only 16 (only appeared at 8 week or after 8 week) out of 69 identified metabolites between 8th week AAN and control groups after observable histological kidney damage and conventional clinical chemistry indications of nephrotoxicity. Heatmap displays of the most significantly changes from 16 metabolites. The colour of each section is proportional to the significance of alternation of metabolites in kidney tissue. Green indicates reduction, red indicates increase compared to control group. Columns represent individual experiments and rows represent each identified metabolites from AAN and control groups in the 8th week. (B) VIP scores with expression heat map from PLS-DA analysis. PLS-DA analysis was constructed with signature metabolites from AAN and control rats. Red and green indicated increased and decreased levels, respectively. (C) PLS-DA based ROC curves of 8 out of 16 identified metabolites for evaluation of AAN with the individual biomarkers. The associated AUC, sensitivity and specificity values were indicated.
Mentions: Hierarchical cluster analysis and the resulting heat map revealed that among the 69 metabolites which were significantly altered at week 8 and beyond. Sixteen of these metabolites were markedly altered in the AAN group at week 8 only (Fig. 5A). The cluster diagram revealed that two groups could be separated completely by these sixteen sleeted metabolites with VIP scores of more than 1.0 (Fig. 5B). To assess the predictive performance of the selected metabolites in the AAN, we calculated the AUC value. Among the above 16 metabolites eight were identified as the top-ranked candidates, with an AUC value of more than 0.85 (Fig. 5C) including phytosphingosine, PC(22:5/14:0), tetracosatetraenoic acid, trimethyltridecanoic acid, lysoPC(16:0), PC(16:0/22:5), TG(14:1/14:0/14:1) and PC(18:2/20:5). As a result, these eight metabolites could potentially be considered as predictive metabolites corresponding with the histological evidence of kidney damage, conventional clinical chemistry and activation of inflammatory, oxidant and fibrotic pathways.

Bottom Line: Data obtained on weeks 8 to 24 revealed progressive tubulointerstitial fibrosis, inflammation, renal dysfunction, activation of NF-κB, TGF-β, and oxidative pathways, impaired Nrf2 system, and profound changes in lipid metabolites including numerous PC, lysoPC, PE, lysoPE, ceramides and triglycerides.In conclusion, exposure to AAI results in dynamic changes in kidney tissue fatty acid, phospholipid, and glycerolipid metabolisms prior to and after the onset of detectable changes in renal function or histology.These findings point to participation of altered tissue lipid metabolism in the pathogenesis of AAN.

View Article: PubMed Central - PubMed

Affiliation: 1] Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, the College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China [2] Division of Nephrology and Hypertension, School of Medicine, University of California, Irvine, MedSci 1, C352, UCI Campus, Irvine, California, 92897, USA.

ABSTRACT
Alternative medicines are commonly used for the disease prevention and treatment worldwide. Aristolochic acid (AAI) nephropathy (AAN) is a common and rapidly progressive interstitial nephropathy caused by ingestion of Aristolochia herbal medications. Available data on pathophysiology and molecular mechanisms of AAN are limited and were explored here. SD rats were randomized to AAN and control groups. AAN group was treated with AAI by oral gavage for 12 weeks and observed for additional 12 weeks. Kidneys were processed for histological evaluation, Western blotting, and metabolomics analyses using UPLC-QTOF/HDMS. The concentrations of two phosphatidylcholines, two diglycerides and two acyl-carnitines were significantly altered in AAI treated rats at week 4 when renal function and histology were unchanged. Data obtained on weeks 8 to 24 revealed progressive tubulointerstitial fibrosis, inflammation, renal dysfunction, activation of NF-κB, TGF-β, and oxidative pathways, impaired Nrf2 system, and profound changes in lipid metabolites including numerous PC, lysoPC, PE, lysoPE, ceramides and triglycerides. In conclusion, exposure to AAI results in dynamic changes in kidney tissue fatty acid, phospholipid, and glycerolipid metabolisms prior to and after the onset of detectable changes in renal function or histology. These findings point to participation of altered tissue lipid metabolism in the pathogenesis of AAN.

No MeSH data available.


Related in: MedlinePlus