Rhubarb Protect Against Tubulointerstitial Fibrosis by Inhibiting TGF-β/Smad Pathway and Improving Abnormal Metabolome in Chronic Kidney Disease

Abstract

Tubulointerstitial fibrosis is the final common pathway for all kidney diseases leading to chronic kidney disease (CKD). TGF-β/Smad signaling pathway plays a key role in renal fibrosis. Previous studies have revealed that rhubarb extracts attenuated the increase of transforming growth factor-β 1 (TGF-β1) in CKD rats. To gain an in-depth insight into the mechanism of the anti-fibrotic activities of the rhubarb extracts, we investigated the influence of rhubarb extracts on TGF-β/Smad signaling pathway and the influence on metabolome in a rat model of CKD with adenine-induced chronic tubulointerstitial nephropathy. Male Sprague-Dawley rats were divided into four groups, including control, CKD, CKD + petroleum ether extract, CKD + ethyl acetate extract, and CKD + n-butanol extract groups. Kidneys harvested on the week three were evaluated for renal fibrosis, the expression of proteins in TGF-β/Smad signaling pathway and metabolomic study. We found rhubarb extracts suppressed TGF-β/Smad3-mediated renal fibrosis by reducing the TGF-β1, transforming growth factor-β receptor I (TGF-β RI), transforming growth factor-β receptor II (TGF-β RII), Smad2, p-Smad2, Smad3, p-Smad3, and Smad4, meanwhile increased Smad7. In addition, rhubarb extracts mitigated renal injury and dysfunction, and either fully or partially reversed the abnormalities of tissue metabolites. Thus, rebalancing the disorder of TGF-β/Smad signaling and metabolic dysfunction by treatment with rhubarb extracts may represent as an effective therapy for CKD associated with fibrosis.

Discrimination of Different Parts of Saffron by Metabolomic‐Based Ultra‐Performance Liquid Chromatography Coupled with High‐Definition Mass Spectrometry

“…Metabolomics technique has been extensively applied to the study of TCM and natural products . In agreement with the holistic thinking of TCM, metabonomics has shown potential to reveal the biological foundation and mechanism of TCM …”

“…[37 -40] In agreement with the holistic thinking of TCM, metabonomics has shown potential to reveal the biological foundation and mechanism of TCM. [41][42][43][44][45][46][47] The crocin family is the particular ingredients that occur naturally in stigmas of saffron when compared with other parts. According to the pathway of crocin Figure 5), crocetin can be converted into glucosyl crocetin and finally transferred into crocin.…”

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

“…Natural products and their relevant secondary metabolites have been proven to be the fertile ground for drug discovery and pharmaceutical exploitation [31,62,115]. Moreover, recent advances of powerful analytical platforms based on genomics, proteomics and metabolomics as well as bioinformatics have been ubiquitously employed to reveal the bioactivities of myriad natural products [116][117][118][119]. A growing body of studies supported that natural products should be revisited since the side effects of available commercial drugs brought risks and severely restricted their use.…”

Functional Metabolomics Analysis Elucidating the Metabolic Biomarker and Key Pathway Change Associated With the Chronic Glomerulonephritis and Revealing Action Mechanism of Rhein

“…The prevalence of chronic kidney disease is increasing year by year and has become a global public health problem. In recent years, the technology of metabolomics has been widely used in the research of cardiovascular disease, liver disease, tumor, and other diseases, but the research of chronic kidney disease based on metabolomics technology is still relatively few (Zhang et al, 2015;Sun et al, 2016;Zhang Z. H. et al, 2016;Zhang Z. H. et al, 2018). Most of them focus on animal models, and there are few clinical studies.…”