Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression
Hua Chen,
Gang Cao,
Dan-Qian Chen,
Ming Wang,
Nosratola D. Vaziri,
Zhi-Hao Zhang,
Jia-Rong Mao,
Xu Bai,
Ying-Yong Zhao
Affiliations
Hua Chen
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
Gang Cao
Research Center of TCM Processing Technology, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
Dan-Qian Chen
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
Ming Wang
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
Nosratola D. Vaziri
Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, MedSci 1, C352, UCI Campus, Irvine, CA 92897, USA
Zhi-Hao Zhang
National Center for Natural Products Research, Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA
Jia-Rong Mao
Department of Nephrology, the Affiliated Hospital of Shaanxi Institute of Traditional Chinese Medicine, No. 2 Xihuamen, Xi’an, Shaanxi 710003, China
Xu Bai
Solution Centre, Waters Technologies (Shanghai) Ltd., No. 1000 Jinhai Road, Shanghai 201203, PR China
Ying-Yong Zhao
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
Early detection is critical in prevention and treatment of kidney disease. However currently clinical laboratory and histopathological tests do not provide region-specific and accurate biomarkers for early detection of kidney disease. The present study was conducted to identify sensitive biomarkers for early detection and progression of tubulo-interstitial nephropathy in aristolochic acid I-induced rats at weeks 4, 8 and 12. Biomarkers were validated using aristolochic acid nephropathy (AAN) rats at week 24, adenine-induced chronic kidney disease (CKD) rats and CKD patients. Compared with control rats, AAN rats showed anemia, increased serum urea and creatinine, progressive renal interstitial fibrosis, activation of nuclear factor-kappa B, and up-regulation of pro-inflammatory, pro-oxidant, and pro-fibrotic proteins at weeks 8 and 12. However, no significant difference was found at week 4. Metabolomics identified 12-ketodeoxycholic acid, taurochenodesoxycholic acid, LPC(15:0) and docosahexaenoic acid as biomarkers for early detection of tubulo-interstitial nephropathy. With prolonging aristolochic acid I exposure, LPE(20:2), cholic acid, chenodeoxycholic acid and LPC(17:0) were identified as biomarkers for progression from early to advanced AAN and lysoPE(22:5), indoxyl sulfate, uric acid and creatinine as biomarkers of advanced AAN. These biomarkers were reversed by treatment of irbesartan and ergone in AAN rats at week 24 and adenine-induced CKD rats. In addition, these biomarkers were also reversed by irbesartan treatment in CKD patients.
