Identification of key metabolic changes in renal interstitial fibrosis rats using metabonomics and pharmacology

Liangcai Zhao,Shixian Liao,Hongchang Gao,Jiansong Ji,Hong Zheng,Minjiang Chen,Minjian Dong,Yao Du,Qi Zhou

doi:10.1038/srep27194

Liangcai Zhao, Shixian Liao + Show 7 more

Open Access

https://doi.org/10.1038/srep27194

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Abstract

Renal fibrosis is one of the important pathways involved in end-stage renal failure. Investigating the metabolic changes in the progression of disease may enhance the understanding of its pathogenesis and therapeutic information. In this study, 1H-nuclear magnetic resonance (NMR)-based metabonomics was firstly used to screen the metabolic changes in urine and kidney tissues of renal interstitial fibrotic rats induced by unilateral ureteral obstruction (UUO), at 7, 14, 21, and 28 days after operation, respectively. The results revealed that reduced levels of bioenergy synthesis and branched chain amino acids (BCAAs), as well as elevated levels of indoxyl sulfate (IS) are involved in metabolic alterations of renal fibrosis rats. Next, by pharmacological treatment we found that reduction of IS levels could prevent the renal fibrotic symptoms. Therefore, we suggested that urinary IS may be used as a potential biomarker for the diagnosis of renal fibrosis, and a therapeutic target for drugs. Novel attempt combining metabonomics and pharmacology was established that have ability to provide more systematic diagnostic and therapeutic information of diseases.

Highlights

Renal fibrosis is one of the important pathways involved in end-stage renal failure
The pathological mechanisms of renal fibrosis include disproportionate accumulation of extracellular matrix, proliferation of interstitial fibroblasts that replace kidney parenchyma, tubular dilation and atrophy, and infiltration of inflammatory cells resulting in tubular cell apoptosis and necrosis[1,2,3]
Using nuclear magnetic resonance (NMR)-based metabonomics, we comprehensively investigated the metabolic characteristics during diabetes evolution and found metabonomics was a valuable approach for providing novel insights into the pathogenesis of diabetes mellitus and its complications[7,8,9]

Summary

Introduction

Renal fibrosis is one of the important pathways involved in end-stage renal failure. Investigating the metabolic changes in the progression of disease may enhance the understanding of its pathogenesis and therapeutic information. 1H-nuclear magnetic resonance (NMR)-based metabonomics was firstly used to screen the metabolic changes in urine and kidney tissues of renal interstitial fibrotic rats induced by unilateral ureteral obstruction (UUO), at 7, 14, 21, and 28 days after operation, respectively. Zhao et al identified perturbations of bile acid metabolism and phospholipid metabolism were closely related to chronic renal failure rats induced by adenine using metabonomics[12] They screened potential biomarkers and drug targets involved in the disease[13,14]. We studied the serum metabolic profiling of renal fibrotic rats induced by UUO17, and revealed enhanced pathways of lipid and ketone body synthesis, and disturbed tricarboxylic acid (TCA) cycle were partly contribute to the pathogenesis of renal fibrosis. Which metabolites and pathways are dominant during the pathogenic evolution of renal fibrosis needs further exploration

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