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.
Highlights
The progression of chronic kidney disease (CKD) is an increasingly common condition and a considerable proportion of CKD eventually progress to end-stage renal disease (ESRD), a devastating condition that requires life-long treatments with dialysis or renal allograft transplantation
ethyl acetate extract (EA)-treated (EA+CKD) and n-butanol extract (BU)-treated (BU+CKD) groups showed a significant decrease in serum triglyceride, CREA and urea concentrations in relative to CKD group
Kidney tissues from the CKD rats showed severe tubular dilatation, tubular atrophy, and widened interstitial space with severe inflammatory cell infiltration
Summary
The progression of CKD is an increasingly common condition and a considerable proportion of CKD eventually progress to end-stage renal disease (ESRD), a devastating condition that requires life-long treatments with dialysis or renal allograft transplantation. Tubulointerstitial fibrosis is considered to be the final common pathway for all kidney diseases leading to chronic renal failure (Zeisberg and Neilson, 2010). Tubulointerstitial fibrosis is a dynamic process including four overlapping phases: infiltration of inflammatory cells, fibroblast activation and expansion from various sources, production and deposition of a large amount of ECM components, and tubular atrophy and microvascular rarefaction (Liu, 2011). Any of these pathologic features can contribute to the progression of tubulointerstitial fibrosis in its own unique way. Process of tubulointerstitial fibrosis involves the interaction of a variety of cytokines and multiple signaling pathways, which leads to tubular atrophy, tubulointerstitial fibrosis and eventually loss of kidney function (Boor et al, 2010)
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